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Sample records for varying notch1 signal

  1. Effects of varying Notch1 signal strength on embryogenesis and vasculogenesis in compound mutant heterozygotes

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    Ge Changhui

    2010-03-01

    Full Text Available Abstract Background Identifying developmental processes regulated by Notch1 can be addressed in part by characterizing mice with graded levels of Notch1 signaling strength. Here we examine development in embryos expressing various combinations of Notch1 mutant alleles. Mice homozygous for the hypomorphic Notch112f allele, which removes the single O-fucose glycan in epidermal growth factor-like repeat 12 (EGF12 of the Notch1 ligand binding domain (lbd, exhibit reduced growth after weaning and defective T cell development. Mice homozygous for the inactive Notch1lbd allele express Notch1 missing an ~20 kDa internal segment including the canonical Notch1 ligand binding domain, and die at embryonic day ~E9.5. The embryonic and vascular phenotypes of compound heterozygous Notch112f/lbd embryos were compared with Notch1+/12f, Notch112f/12f, and Notch1lbd/lbd embryos. Embryonic stem (ES cells derived from these embryos were also examined in Notch signaling assays. While Notch1 signaling was stronger in Notch112f/lbd compound heterozygotes compared to Notch1lbd/lbd embryos and ES cells, Notch1 signaling was even stronger in embryos carrying Notch112f and a null Notch1 allele. Results Mouse embryos expressing the hypomorphic Notch112f allele, in combination with the inactive Notch1lbd allele which lacks the Notch1 ligand binding domain, died at ~E11.5-12.5. Notch112f/lbd ES cells signaled less well than Notch112f/12f ES cells but more strongly than Notch1lbd/lbd ES cells. However, vascular defects in Notch112f/lbd yolk sac were severe and similar to Notch1lbd/lbd yolk sac. By contrast, vascular disorganization was milder in Notch112f/lbd compared to Notch1lbd/lbd embryos. The expression of Notch1 target genes was low in Notch112f/lbd yolk sac and embryo head, whereas Vegf and Vegfr2 transcripts were increased. The severity of the compound heterozygous Notch112f/lbd yolk sac phenotype suggested that the allelic products may functionally interact. By

  2. Characterization of Notch1 antibodies that inhibit signaling of both normal and mutated Notch1 receptors.

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    Miguel Aste-Amézaga

    2010-02-01

    Full Text Available Notch receptors normally play a key role in guiding a variety of cell fate decisions during development and differentiation of metazoan organisms. On the other hand, dysregulation of Notch1 signaling is associated with many different types of cancer as well as tumor angiogenesis, making Notch1 a potential therapeutic target.Here we report the in vitro activities of inhibitory Notch1 monoclonal antibodies derived from cell-based and solid-phase screening of a phage display library. Two classes of antibodies were found, one directed against the EGF-repeat region that encompasses the ligand-binding domain (LBD, and the second directed against the activation switch of the receptor, the Notch negative regulatory region (NRR. The antibodies are selective for Notch1, inhibiting Jag2-dependent signaling by Notch1 but not by Notch 2 and 3 in reporter gene assays, with EC(50 values as low as 5+/-3 nM and 0.13+/-0.09 nM for the LBD and NRR antibodies, respectively, and fail to recognize Notch4. While more potent, NRR antibodies are incomplete antagonists of Notch1 signaling. The antagonistic activity of LBD, but not NRR, antibodies is strongly dependent on the activating ligand. Both LBD and NRR antibodies bind to Notch1 on human tumor cell lines and inhibit the expression of sentinel Notch target genes, including HES1, HES5, and DTX1. NRR antibodies also strongly inhibit ligand-independent signaling in heterologous cells transiently expressing Notch1 receptors with diverse NRR "class I" point mutations, the most common type of mutation found in human T-cell acute lymphoblastic leukemia (T-ALL. In contrast, NRR antibodies failed to antagonize Notch1 receptors bearing rare "class II" or "class III" mutations, in which amino acid insertions generate a duplicated or constitutively sensitive metalloprotease cleavage site. Signaling in T-ALL cell lines bearing class I mutations is partially refractory to inhibitory antibodies as compared to cell

  3. Notch 1 signaling regulates peripheral T cell activation.

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    Eagar, Todd N; Tang, Qizhi; Wolfe, Michael; He, Yiping; Pear, Warren S; Bluestone, Jeffrey A

    2004-04-01

    Notch signaling has been identified as an important regulator of leukocyte differentiation and thymic maturation. Less is known about the role of Notch signaling in regulating mature T cells. We examined the role of Notch 1 in regulating peripheral T cell activity in vitro and in vivo. Coligation of Notch 1 together with TCR and CD28 resulted in a dramatic inhibition of T cell activation, proliferation, and cytokine production. This effect was dependent on presenilin activity and induced the expression of HES-1, suggestive of Notch 1 signaling. Biochemical analysis demonstrated an inhibition of AKT and GSK3beta phosphorylation following Notch 1 engagement while other biochemical signals such as TCR and ERK phosphorylation remained intact. Similar effects were observed in vivo in an adoptive transfer model. Therefore, Notch 1 signaling may play an important role in regulating naive T cell activation and homeostasis.

  4. Roles of Notch1 Signaling in Regulating Satellite Cell Fates Choices and Postnatal Skeletal Myogenesis.

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    Shan, Tizhong; Xu, Ziye; Wu, Weiche; Liu, Jiaqi; Wang, Yizhen

    2017-11-01

    Adult skeletal muscle stem cells, also called satellite cells, are indispensable for the growth, maintenance, and regeneration of the postnatal skeletal muscle. Satellite cells, predominantly quiescent in mature resting muscles, are activated after skeletal muscle injury or degeneration. Notch1 signaling is an evolutionarily conserved pathway that plays crucial roles in satellite cells homeostasis and postnatal skeletal myogenesis and regeneration. Activation of Notch1 signaling promotes the muscle satellite cells quiescence and proliferation, but inhibits differentiation of muscle satellite cells. Notably, the new roles of Notch1 signaling during late-stage of skeletal myogenesis including in post-differentiation myocytes and post-fusion myotubes have been recently reported. Here, we mainly review and discuss the regulatory roles of Notch1 in regulating satellite cell fates choices and skeletal myogenesis. J. Cell. Physiol. 232: 2964-2967, 2017. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  5. Notch1 regulates hippocampal plasticity through interaction with the Reelin pathway, glutamatergic transmission and CREB signaling

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    Emanuele eBrai

    2015-11-01

    Full Text Available Notch signaling plays a crucial role in adult brain function such as synaptic plasticity, memory and olfaction. Several reports suggest an involvement of this pathway in neurodegenerative dementia. Yet, to date, the mechanism underlying Notch activity in mature neurons remains unresolved. In this work, we investigate how Notch regulates synaptic potentiation and contributes to the establishment of memory in mice. We observe that Notch1 is a postsynaptic receptor with functional interactions with the Reelin receptor, ApoER2, and the ionotropic receptor, NMDAR. Targeted loss of Notch1 in the hippocampal CA fields affects Reelin signaling by influencing Dab1 expression and impairs the synaptic potentiation achieved through Reelin stimulation. Further analysis indicates that loss of Notch1 affects the expression and composition of the NMDAR but not AMPAR. Glutamatergic signaling is further compromised through downregulation of CamKII and its secondary and tertiary messengers resulting in reduced CREB signaling. Our results identify Notch1 as an important regulator of mechanisms involved in synaptic plasticity and memory formation. These findings emphasize the possible involvement of this signaling receptor in dementia.

  6. Activation of the Notch-1 signaling pathway may be involved in intracerebral hemorrhage-induced reactive astrogliosis in rats.

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    Zhong, Jian-Hua; Zhou, Hua-Jun; Tang, Tao; Cui, Han-Jin; Yang, A-Li; Zhang, Qi-Mei; Zhou, Jing-Hua; Zhang, Qiang; Gong, Xun; Zhang, Zhao-Hui; Mei, Zhi-Gang

    2017-10-27

    OBJECTIVE Reactive astrogliosis, a key feature that is characterized by glial proliferation, has been observed in rat brains after intracerebral hemorrhage (ICH). However, the mechanisms that control reactive astrogliosis formation remain unknown. Notch-1 signaling plays a critical role in modulating reactive astrogliosis. The purpose of this paper was to establish whether Notch-1 signaling is involved in reactive astrogliosis after ICH. METHODS ICH was induced in adult male Sprague-Dawley rats via stereotactic injection of autologous blood into the right globus pallidus. N-[ N-(3,5-difluorophenacetyl)-l-alanyl]- S-phenylglycine t-butyl ester (DAPT) was injected into the lateral ventricle to block Notch-1 signaling. The rats' brains were perfused to identify proliferating cell nuclear antigen (PCNA)-positive/GFAP-positive nuclei. The expression of GFAP, Notch-1, and the activated form of Notch-1 (Notch intracellular domain [NICD]) and its ligand Jagged-1 was assessed using immunohistochemical and Western blot analyses, respectively. RESULTS Notch-1 signaling was upregulated and activated after ICH as confirmed by an increase in the expression of Notch-1 and NICD and its ligand Jagged-1. Remarkably, blockade of Notch-1 signaling with the specific inhibitor DAPT suppressed astrocytic proliferation and GFAP levels caused by ICH. In addition, DAPT improved neurological outcome after ICH. CONCLUSIONS Notch-1 signaling is a critical regulator of ICH-induced reactive astrogliosis, and its blockage may be a potential therapeutic strategy for hemorrhagic injury.

  7. Role of Notch-1 signaling in ethanol induced PC12 apoptosis | Li ...

    African Journals Online (AJOL)

    Chronic alcoholic dementia has crucial role in progress of neurodegenerative disease and affects a large portion of our aging population. Neuronal cell apoptosis may be a contributing factor of neurodegenerative disease (ND) and Alzheimer's disease (AD). Previous researches have indicated that Notch-1 signaling ...

  8. Inhibition of fibroblast growth by Notch1 signaling is mediated by induction of Wnt11-dependent WISP-1.

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    Liu, Zhao-Jun; Li, Yan; Tan, Yurong; Xiao, Min; Zhang, Jialin; Radtke, Freddy; Velazquez, Omaida C

    2012-01-01

    Fibroblasts are an integral component of stroma and important source of growth factors and extracellular matrix (ECM). They play a prominent role in maintaining tissue homeostasis and in wound healing and tumor growth. Notch signaling regulates biological function in a variety of cells. To elucidate the physiological function of Notch signaling in fibroblasts, we ablated Notch1 in mouse (Notch1(Flox/Flox)) embryonic fibroblasts (MEFs). Notch1-deficient (Notch1(-/-)) MEFs displayed faster growth and motility rate compared to Notch1(Flox/Flox) MEFs. Such phenotypic changes, however, were reversible by reconstitution of Notch1 activation via overexpression of the intracellular domain of Notch1 (NICD1) in Notch1-deficient MEFs. In contrast, constitutive activation of Notch1 signaling by introducing NICD1 into primary human dermal fibroblasts (FF2441), which caused pan-Notch activation, inhibited cell growth and motility, whereas cellular inhibition was relievable when the Notch activation was countered with dominant-negative mutant of Master-mind like 1 (DN-MAML-1). Functionally, "Notch-activated" stromal fibroblasts could inhibit tumor cell growth/invasion. Moreover, Notch activation induced expression of Wnt-induced secreted proteins-1 (WISP-1/CCN4) in FF2441 cells while deletion of Notch1 in MEFs resulted in an opposite effect. Notably, WISP-1 suppressed fibroblast proliferation, and was responsible for mediating Notch1's inhibitory effect since siRNA-mediated blockade of WISP-1 expression could relieve cell growth inhibition. Notch1-induced WISP-1 expression appeared to be Wnt11-dependent, but Wnt1-independent. Blockade of Wnt11 expression resulted in decreased WISP-1 expression and liberated Notch-induced cell growth inhibition. These findings indicated that inhibition of fibroblast proliferation by Notch pathway activation is mediated, at least in part, through regulating Wnt1-independent, but Wnt11-dependent WISP-1 expression.

  9. Inhibition of fibroblast growth by Notch1 signaling is mediated by induction of Wnt11-dependent WISP-1.

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    Zhao-Jun Liu

    Full Text Available Fibroblasts are an integral component of stroma and important source of growth factors and extracellular matrix (ECM. They play a prominent role in maintaining tissue homeostasis and in wound healing and tumor growth. Notch signaling regulates biological function in a variety of cells. To elucidate the physiological function of Notch signaling in fibroblasts, we ablated Notch1 in mouse (Notch1(Flox/Flox embryonic fibroblasts (MEFs. Notch1-deficient (Notch1(-/- MEFs displayed faster growth and motility rate compared to Notch1(Flox/Flox MEFs. Such phenotypic changes, however, were reversible by reconstitution of Notch1 activation via overexpression of the intracellular domain of Notch1 (NICD1 in Notch1-deficient MEFs. In contrast, constitutive activation of Notch1 signaling by introducing NICD1 into primary human dermal fibroblasts (FF2441, which caused pan-Notch activation, inhibited cell growth and motility, whereas cellular inhibition was relievable when the Notch activation was countered with dominant-negative mutant of Master-mind like 1 (DN-MAML-1. Functionally, "Notch-activated" stromal fibroblasts could inhibit tumor cell growth/invasion. Moreover, Notch activation induced expression of Wnt-induced secreted proteins-1 (WISP-1/CCN4 in FF2441 cells while deletion of Notch1 in MEFs resulted in an opposite effect. Notably, WISP-1 suppressed fibroblast proliferation, and was responsible for mediating Notch1's inhibitory effect since siRNA-mediated blockade of WISP-1 expression could relieve cell growth inhibition. Notch1-induced WISP-1 expression appeared to be Wnt11-dependent, but Wnt1-independent. Blockade of Wnt11 expression resulted in decreased WISP-1 expression and liberated Notch-induced cell growth inhibition. These findings indicated that inhibition of fibroblast proliferation by Notch pathway activation is mediated, at least in part, through regulating Wnt1-independent, but Wnt11-dependent WISP-1 expression.

  10. Notch1-Dll4 signaling and mechanical force regulate leader cell formation during collective cell migration

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    Riahi, Reza; Sun, Jian; Wang, Shue; Long, Min; Zhang, Donna D.; Wong, Pak Kin

    2015-01-01

    At the onset of collective cell migration, a subset of cells within an initially homogenous population acquires a distinct “leader” phenotype with characteristic morphology and motility. However, the factors driving leader cell formation as well as the mechanisms regulating leader cell density during the migration process remain to be determined. Here, we use single cell gene expression analysis and computational modeling to show that leader cell identity is dynamically regulated by Dll4 signaling through both Notch1 and cellular stress in a migrating epithelium. Time-lapse microscopy reveals that Dll4 is induced in leader cells after the creation of the cell-free region and leader cells are regulated via Notch1-Dll4 lateral inhibition. Furthermore, mechanical stress inhibits Dll4 expression and leader cell formation in the monolayer. Collectively, our findings suggest that a reduction of mechanical force near the boundary promotes Notch1-Dll4 signaling to dynamically regulate the density of leader cells during collective cell migration. PMID:25766473

  11. Notch1-Dll4 signalling and mechanical force regulate leader cell formation during collective cell migration.

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    Riahi, Reza; Sun, Jian; Wang, Shue; Long, Min; Zhang, Donna D; Wong, Pak Kin

    2015-03-13

    At the onset of collective cell migration, a subset of cells within an initially homogenous population acquires a distinct 'leader' phenotype with characteristic morphology and motility. However, the factors driving the leader cell formation as well as the mechanisms regulating leader cell density during the migration process remain to be determined. Here we use single-cell gene expression analysis and computational modelling to show that the leader cell identity is dynamically regulated by Dll4 signalling through both Notch1 and cellular stress in a migrating epithelium. Time-lapse microscopy reveals that Dll4 is induced in leader cells after the creation of the cell-free region and leader cells are regulated via Notch1-Dll4 lateral inhibition. Furthermore, mechanical stress inhibits Dll4 expression and leader cell formation in the monolayer. Collectively, our findings suggest that a reduction of mechanical force near the boundary promotes Notch1-Dll4 signalling to dynamically regulate the density of leader cells during collective cell migration.

  12. Activation of Notch1 signaling in stromal fibroblasts inhibits melanoma growth by upregulating WISP-1.

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    Shao, H; Cai, L; Grichnik, J M; Livingstone, A S; Velazquez, O C; Liu, Z-J

    2011-10-20

    The tumor microenvironment is emerging as an important target for cancer therapy. Fibroblasts (Fbs) within the tumor stroma are critically involved in promoting tumor growth and angiogenesis through secretion of soluble factors, synthesis of extracellular matrix and direct cell-cell interaction. In this work, we aim to alter the biological activity of stromal Fbs by modulating the Notch1 signaling pathway. We show that Fbs engineered to constitutively activate the Notch1 pathway significantly inhibit melanoma growth and tumor angiogenesis. We determine that the inhibitory effect of 'Notch-engineered' Fbs is mediated by increased secretion of Wnt-induced secreted protein-1 (WISP-1) as the effects of Notch1 activation in Fbs are reversed by shRNA-mediated blockade of WISP-1. When 'Notch-engineered' Fbs are co-grafted with melanoma cells in SCID mice, shRNA-mediated blockade of WISP-1 reverses the tumor-suppressive phenotype of the 'Notch-engineered' Fbs, significantly increases melanoma growth and tumor angiogenesis. Consistent with these findings, supplement of recombinant WISP-1 protein inhibits melanoma cell growth in vitro. In addition, WISP-1 is modestly expressed in melanoma-activated Fbs but highly expressed in inactivated Fbs. Evaluation of human melanoma skin biopsies indicates that expression of WISP-1 is significantly lower in melanoma nests and surrounding areas filled with infiltrated immune cells than in the adjacent dermis unaffected by the melanoma. Overall, our study shows that constitutive activation of the Notch1 pathway confers Fbs with a suppressive phenotype to melanoma growth, partially through WISP-1. Thus, targeting tumor stromal Fbs by activating Notch signaling and/or increasing WISP-1 may represent a novel therapeutic approach to combat melanoma.

  13. Structure of the Notch1-negative regulatory region: implications for normal activation and pathogenic signaling in T-ALL

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    Gordon, Wendy R.; Roy, Monideepa; Vardar-Ulu, Didem; Garfinkel, Megan; Mansour, Marc R.; Aster, Jon C.; Blacklow, Stephen C.; (BWH); (Wellesley); (UCL)

    2009-09-02

    Proteolytic resistance of Notch prior to ligand binding depends on the structural integrity of a negative regulatory region (NRR) of the receptor that immediately precedes the transmembrane segment. The NRR includes the 3 Lin12/Notch repeats and the juxtamembrane heterodimerization domain, the region of Notch1 most frequently mutated in T-cell acute lymphoblastic leukemia lymphoma (T-ALL). Here, we report the x-ray structure of the Notch1 NRR in its autoinhibited conformation. A key feature of the Notch1 structure that maintains its closed conformation is a conserved hydrophobic plug that sterically occludes the metalloprotease cleavage site. Crystal packing interactions involving a highly conserved, exposed face on the third Lin12/Notch repeat suggest that this site may normally be engaged in intermolecular or intramolecular protein-protein interactions. The majority of known T-ALL-associated point mutations map to residues in the hydrophobic interior of the Notch1 NRR. A novel mutation (H1545P), which alters a residue at the crystal-packing interface, leads to ligand-independent increases in signaling in reporter gene assays despite only mild destabilization of the NRR, suggesting that it releases the autoinhibitory clamp on the heterodimerization domain imposed by the Lin12/Notch repeats. The Notch1 NRR structure should facilitate a search for antibodies or compounds that stabilize the autoinhibited conformation.

  14. Effect of Mesenchymal Stem Cells and a Novel Curcumin Derivative on Notch1 Signaling in Hepatoma Cell Line

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    Mohamed Talaat Abdel Aziz

    2013-01-01

    Full Text Available This study was conducted to evaluate the effect of mesenchymal stem cells (MSCs and a novel curcumin derivative (NCD on HepG2 cells (hepatoma cell line and to investigate their effect on Notch1 signaling pathway target genes. HepG2 cells were divided into HepG2 control group, HepG2 cells treated with MSC conditioned medium (MSCs CM, HepG2 cells treated with a NCD, HepG2 cells treated with MSCs CM and NCD, and HepG2 cells treated with MSCs CM (CM of MSCs pretreated with a NCD. Expression of Notch1, Hes1, VEGF, and cyclin D1 was assessed by real-time, reverse transcription-polymerase chain reaction (RT-PCR in HepG2 cells. In addition, HepG2 proliferation assay was performed in all groups. Notch1 and its target genes (Hes1 and cyclin D1 were downregulated in all treated groups with more suppressive effect in the groups treated with both MSCs and NCD. Also, treated HepG2 cells showed significant decrease in cell proliferation rate. These data suggest that modulation of Notch1 signaling pathway by MSCs and/or NCD can be considered as a therapeutic target in HCC.

  15. Voluntary running-enhanced synaptic plasticity, learning and memory are mediated by Notch1 signal pathway in C57BL mice.

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    Zhang, Xiaochen; Yang, Chunxiao; Gao, Jing; Yin, Hongqiang; Zhang, Hui; Zhang, Tao; Yang, Zhuo

    2018-03-01

    It is well known that voluntary running can enhance synaptic plasticity and improve learning and memory abilities. The Notch1 receptor is also reported to be associated with these processes, but its role in running-induced alterations is unclear. In this study, we aimed to investigate whether the Notch1 signalling pathway was involved in voluntary running-induced enhancement of synaptic plasticity, learning and memory. Notch1 heterozygous deficient (Notch1 +/- ) mice and wildtype (WT) C57BL littermates were randomly divided into runner group and non-runner group. Mice were given free access to running wheels for 14 days in both the Notch1 +/- runner group and the WT runner group. Our results demonstrate that Notch1 knockdown impairs the performance in the novel object recognition (NOR) test and Morris water maze test and decreases the synaptic plasticity. Voluntary running improves spatial learning and memory abilities, promotes synaptic plasticity and increases expressions of postsynaptic proteins in WT mice but not in Notch1 +/- mice. Our results suggest that Notch1 plays a vital role in spatial learning and memory, synaptic plasticity under normal physiological conditions and voluntary running conditions. These findings will set the groundwork and fill in some gaps for understanding the role of Notch1 signalling in voluntary running-induced phenomena.

  16. Wnt5a controls Notch1 signaling through CaMKII-mediated degradation of the SMRT corepressor protein.

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    Ann, Eun-Jung; Kim, Hwa-Young; Seo, Mi-Sun; Mo, Jung-Soon; Kim, Mi-Yeon; Yoon, Ji-Hye; Ahn, Ji-Seon; Park, Hee-Sae

    2012-10-26

    Serine-threonine Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) is the key component in noncanonical Wnt5a signaling and has been shown to regulate its signaling. In this study, we found that CaMKII induced by Wnt5a remarkably reduced the protein stability of the silencing mediator of retinoic acid and thyroid hormone receptor (SMRT), a co-repressor of Notch signaling, through proteasomal degradation. Wnt5a was found to enhance Notch1 intracellular domain (Notch1-IC) transcription activity, which could be inhibited by treatment with KN93, a CaMKII inhibitor. The kinase activity of CaMKII was essential for the activation of Notch signaling. We also determined that CaMKII could enhance the association between Notch1-IC and RBP-Jk. Furthermore, the physical association between RBP-Jk and SMRT was substantially suppressed by CaMKII. We demonstrated that CaMKII directly bound and phosphorylated SMRT at Ser-1407, thereby facilitating SMRT translocation from the nucleus to the cytoplasm and proteasome-dependent degradation. These results suggest that CaMKII down-regulated the protein stability of SMRT through proteasomal degradation.

  17. Wnt5a Controls Notch1 Signaling through CaMKII-mediated Degradation of the SMRT Corepressor Protein*

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    Ann, Eun-Jung; Kim, Hwa-Young; Seo, Mi-Sun; Mo, Jung-Soon; Kim, Mi-Yeon; Yoon, Ji-Hye; Ahn, Ji-Seon; Park, Hee-Sae

    2012-01-01

    Serine-threonine Ca2+/calmodulin-dependent protein kinase II (CaMKII) is the key component in noncanonical Wnt5a signaling and has been shown to regulate its signaling. In this study, we found that CaMKII induced by Wnt5a remarkably reduced the protein stability of the silencing mediator of retinoic acid and thyroid hormone receptor (SMRT), a co-repressor of Notch signaling, through proteasomal degradation. Wnt5a was found to enhance Notch1 intracellular domain (Notch1-IC) transcription activity, which could be inhibited by treatment with KN93, a CaMKII inhibitor. The kinase activity of CaMKII was essential for the activation of Notch signaling. We also determined that CaMKII could enhance the association between Notch1-IC and RBP-Jk. Furthermore, the physical association between RBP-Jk and SMRT was substantially suppressed by CaMKII. We demonstrated that CaMKII directly bound and phosphorylated SMRT at Ser-1407, thereby facilitating SMRT translocation from the nucleus to the cytoplasm and proteasome-dependent degradation. These results suggest that CaMKII down-regulated the protein stability of SMRT through proteasomal degradation. PMID:22888005

  18. Different patterns of NF-κB and Notch1 signaling contribute to tumor-induced lymphangiogenesis of esophageal squamous cell carcinoma

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    Wang Tao

    2011-09-01

    Full Text Available Abstract Background Lymph node involvement and tumor-induced lymphangiogenesis appear as the earliest features of esophageal squamous cell carcinoma (ESCC, although the molecular regulatory mechanisms involved have remained unclear. Our aim was to investigate the contribution of NF-κB and Notch1 signaling to lymph node involvement and tumor-induced lymphangiogenesis in ESCC. Material and methods NF-κB and Notch1 expression in 60 tissue samples of ESCC were assessed by immunohistochemical staining. The correlations of NF-κB and Notch1 with lymph node involvement, lymphatic vessel density (LVD, podoplanin, and vascular endothelial growth factor-C (VEGF-C were further evaluated to determine the association of NF-κB and Notch1 expression with tumor-induced lymphangiogenesis. Results Chi-square tests revealed that NF-κB and Notch1 expression in ESCC tissues were significant associated with lymph node metastasis, LVD, podoplanin, and VEGF-C expression. Strong expression of NF-κB, but weak expression of Notch1, was observed in tumor tissues with lymph nodes involvement (P P P P Conclusion These results suggest that different patterns of NF-κB and Notch1 signaling contribute to lymph nodes metastasis and tumor-induced lymphangiogenesis of ESCC, and reveal that up-regulation of NF-κB is associated with down-regulation of Notch1 in tumor tissue.

  19. Luteolin suppresses angiogenesis and vasculogenic mimicry formation through inhibiting Notch1-VEGF signaling in gastric cancer.

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    Zang, Mingde; Hu, Lei; Zhang, Baogui; Zhu, Zhenglun; Li, Jianfang; Zhu, Zhenggang; Yan, Min; Liu, Bingya

    2017-08-26

    Gastric cancer is a great threat to the health of the people worldwide and lacks effective therapeutic regimens. Luteolin is one of Chinese herbs and presents in many fruits and green plants. In our previous study, we observed that luteolin inhibited cell migration and promoted cell apoptosis in gastric cancer. In the present study, luteolin significantly inhibited tube formation of human umbilical vein endothelial cells (HUVECs) through decreasing cell migration and proliferation of HUVECs in a dose-dependent manner. Vasculogenic mimicry (VM) tubes formed by gastric cancer cells were also inhibited with luteolin treatment. To explore how luteolin inhibited tubes formation, ELISA assay for VEGF was performed. Both of the VEGF secretion from Hs-746T cells and HUVECs were significantly decreased subsequent to luteolin treatment. In addition, cell migration was increased with the interaction between gastric cancer cells and HUVECs in co-culture assays. However, the promoting effects were abolished subsequent to luteolin treatment. Furthermore, luteolin inhibited VEGF secretion through suppressing Notch1 expression in gastric cancer. Overexpression of Notch1 in gastric cancer cells partially rescued the effects on cell migration, proliferation, HUVECs tube formation, and VM formation induced by luteolin treatment. In conclusion, luteolin inhibits angiogenesis and VM formation in gastric cancer through suppressing VEGF secretion dependent on Notch1 expression. Copyright © 2017 Elsevier Inc. All rights reserved.

  20. Decidual vascular endothelial cells promote maternal-fetal immune tolerance by inducing regulatory T cells through canonical Notch1 signaling.

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    Yao, Yanyi; Song, Jieping; Wang, Weipeng; Liu, Nian

    2016-05-01

    Adaptation of the maternal immune response to accommodate the semiallogeneic fetus is necessary for pregnancy success. However, the mechanisms by which the fetus avoids rejection despite expression of paternal alloantigens remain incompletely understood. Regulatory T cells (Treg cells) are pivotal for maintaining immune homeostasis, preventing autoimmune disease and fetus rejection. In this study, we found that maternal decidual vascular endothelial cells (DVECs) sustained Foxp3 expression in resting Treg cells in vitro. Moreover, under in vitro Treg cell induction condition with agonistic antibodies and transforming growth factor (TGF)-β, DVECs promoted Treg cell differentiation from non-Treg conventional T cells. Consistent with the promotion of Treg cell maintenance and differentiation, Treg cell-associated gene expression such as TGF-β, Epstein-Barr-induced gene-3, CD39 and glucocorticoid-induced tumor necrosis factor receptor was also increased in the presence of DVECs. Further study revealed that DVECs expressed Notch ligands such as Jagged-1, Delta-like protein 1 (DLL-1) and DLL-4, while Treg cells expressed Notch1 on their surface. The effects of DVECs on Treg cells was inhibited by siRNA-induced knockdown of expression of Jagged-1 and DLL-1 in DVECs. Downregulation of Notch1 in Treg cells using lentiviral shRNA transduction decreased Foxp3 expression in Treg cells. Adoptive transfer of Notch1-deficient Treg cells increased abortion rate in a murine semiallogeneic pregnancy model. Taken together, our study suggests that maternal DVECs are able to maintain decidual Treg cell identity and promote Treg cell differentiation through activation of Notch1 signal pathway in Treg cells and subsequently inhibit the immune response against semiallogeneic fetuses and preventing spontaneous abortion.

  1. O-GlcNAc on NOTCH1 EGF repeats regulates ligand-induced Notch signaling and vascular development in mammals

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    Sawaguchi, Shogo; Varshney, Shweta; Ogawa, Mitsutaka; Sakaidani, Yuta; Yagi, Hirokazu; Takeshita, Kyosuke; Murohara, Toyoaki; Kato, Koichi; Sundaram, Subha; Stanley, Pamela; Okajima, Tetsuya

    2017-01-01

    The glycosyltransferase EOGT transfers O-GlcNAc to a consensus site in epidermal growth factor-like (EGF) repeats of a limited number of secreted and membrane proteins, including Notch receptors. In EOGT-deficient cells, the binding of DLL1 and DLL4, but not JAG1, canonical Notch ligands was reduced, and ligand-induced Notch signaling was impaired. Mutagenesis of O-GlcNAc sites on NOTCH1 also resulted in decreased binding of DLL4. EOGT functions were investigated in retinal angiogenesis that depends on Notch signaling. Global or endothelial cell-specific deletion of Eogt resulted in defective retinal angiogenesis, with a mild phenotype similar to that caused by reduced Notch signaling in retina. Combined deficiency of different Notch1 mutant alleles exacerbated the abnormalities in Eogt−/− retina, and Notch target gene expression was decreased in Eogt−/−endothelial cells. Thus, O-GlcNAc on EGF repeats of Notch receptors mediates ligand-induced Notch signaling required in endothelial cells for optimal vascular development. DOI: http://dx.doi.org/10.7554/eLife.24419.001 PMID:28395734

  2. Notch-1 Signalling Is Activated in Brain Arteriovenous Malformations in Humans

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    ZhuGe, Qichuan; Zhong, Ming; Zheng, WeiMing; Yang, Guo-Yuan; Mao, XiaoOu; Xie, Lin; Chen, Gourong; Chen, Yongmei; Lawton, Michael T.; Young, William L.; Greenberg, David A.; Jin, Kunlin

    2009-01-01

    A role for the Notch signalling pathway in the formation of arteriovenous malformations during development has been suggested. However, whether Notch signalling is involved in brain arteriovenous malformations in humans remains unclear. Here, we performed immunohistochemistry on surgically resected brain arteriovenous malformations and found that,…

  3. Activation of Notch1 signaling alleviates dysfunction of bone marrow-derived mesenchymal stem cells induced by cigarette smoke extract

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    Cheng Y

    2017-10-01

    Full Text Available Yi Cheng,* Wen Gu,* Guorui Zhang, Xiaoming Li, Xuejun Guo Department of Respiratory Medicine, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China *These authors contributed equally to this work Abstract: Bone marrow-derived mesenchymal stem cells (BM-MSCs are considered attractive therapeutic agents for the treatment of COPD. However, little is known about the impact of Notch on the proliferation, migration, and survival of MSCs in a cigarette smoke (CS microenvironment. Here, we used CS extract to mimic the CS microenvironment in vitro, with the intention to investigate the effect of Notch in regulating proliferation, migration, and survival of BM-MSCs. Rat bone marrow mesenchymal stem cells were infected with lentivirus vector containing the intracellular domain of Notch1 (N1ICD and challenged with CS extract. Cell proliferation was detected by Ki67 staining and expression of cell cycle-related proteins. A transwell assay was used to measure cell migration and the expression of apoptotic proteins was examined. The proliferation of BM-MSCs overexpressing N1ICD significantly increased. Consistently, levels of cyclin D1, p-Rb, and E2F-1 increased in N1ICD overexpressing cells. N1ICD overexpression also increased cell migration compared with the control group. N1ICD overexpression equilibrated the expression of Bax and Bcl-2, and blocked caspase-3 cleavage, contributing to the inhibition of apoptosis. Moreover, blockade of the PI3K/Akt pathway suppressed the aforementioned cytoprotective effects of N1ICD. In conclusion, activation of Notch signaling improved proliferation, migration, and survival of BM-MSCs in a CS microenvironment partly through the PI3K/Akt pathway. Keywords: mesenchymal stem cells, chronic obstructive pulmonary disease, cigarette smoke extract, Notch

  4. Osteoprotegerin inhibits calcification of vascular smooth muscle cell via down regulation of the Notch1-RBP-Jκ/Msx2 signaling pathway.

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    Zhou, Shaoqiong; Fang, Xin; Fang, Xing; Xin, Huaping; Li, Wei; Qiu, Hongyu; Guan, Siming

    2013-01-01

    Vascular calcification is a common pathobiological process which occurs among the elder population and in patients with diabetes and chronic kidney disease. Osteoprotegerin, a secreted glycoprotein that regulates bone mass, has recently emerged as an important regulator of the development of vascular calcification. However, the mechanism is not fully understood. The purpose of this study is to explore novel signaling mechanisms of osteoprotegerin in the osteoblastic differentiation in rat aortic vascular smooth muscle cells (VSMCs). VSMCs were isolated from thoracic aorta of Sprague Dawley rats. Osteoblastic differentiation of VSMCs was induced by an osteogenic medium. We confirmed by Von Kossa staining and direct cellular calcium measurement that mineralization was significantly increased in VSMCs cultured in osteogenic medium; consistent with an enhanced alkaline phosphatase activity. This osteoblastic differentiation in VSMCs was significantly reduced by the addition of osteoprotegerin in a dose responsive manner. Moreover, we identified, by real-time qPCR and western blotting, that expression of Notch1 and RBP-Jκ were significantly up-regulated in VSMCs cultured in osteogenic medium at both the mRNA and protein levels, these effects were dose-dependently abolished by the treatment of osteoprotegerin. Furthermore, we identified that Msx2, a downstream target of the Notch1/RBP-Jκ signaling, was markedly down-regulated by the treatment of osteoprotegerin. Osteoprotegerin inhibits vascular calcification through the down regulation of the Notch1-RBP-Jκ signaling pathway.

  5. Ubiquitination of Notch1 is regulated by MAML1-mediated p300 acetylation of Notch1

    Energy Technology Data Exchange (ETDEWEB)

    Popko-Scibor, Anita E.; Lindberg, Mikael J.; Hansson, Magnus L.; Holmlund, Teresa [Division of Molecular Toxicology, Institute of Environmental Medicine, Karolinska Institutet, 171 77 Stockholm (Sweden); Wallberg, Annika E., E-mail: Annika.Wallberg@ki.se [Division of Molecular Toxicology, Institute of Environmental Medicine, Karolinska Institutet, 171 77 Stockholm (Sweden)

    2011-12-16

    Highlights: Black-Right-Pointing-Pointer p300 acetylates conserved lysines within Notch1 C-terminal nuclear localization signal. Black-Right-Pointing-Pointer MAML1 and CSL, components of Notch transcription complex, increase Notch acetylation. Black-Right-Pointing-Pointer MAML1-dependent acetylation of Notch1 by p300 decreases the ubiquitination of Notch1. Black-Right-Pointing-Pointer CDK8 inhibits Notch acetylation and Notch transcription enhanced by p300. -- Abstract: Earlier studies demonstrated the involvement of the p300 histone acetyltransferase in Notch signaling but the precise mechanisms by which p300 might modulate Notch function remains to be investigated. In this study, we show that p300 acetylates Notch1 ICD in cell culture assay and in vitro, and conserved lysines located within the Notch C-terminal nuclear localization signal are essential for Notch acetylation. MAML1 and CSL, which are components of the Notch transcription complex, enhance Notch acetylation and we suggest that MAML1 increases Notch acetylation by potentiating p300 autoacetylation. Furthermore, MAML1-dependent acetylation of Notch1 ICD by p300 decreases the ubiquitination of Notch1 ICD in cellular assays. CDK8 has been shown to target Notch1 for ubiquitination and proteosomal degradation. We show that CDK8 inhibits Notch acetylation and Notch transcription enhanced by p300. Therefore, we speculate that acetylation of Notch1 might be a mechanism to regulate Notch activity by interfering with ubiquitin-dependent pathways.

  6. Embryonic Stem Cell Differentiation to Functional Arterial Endothelial Cells through Sequential Activation of ETV2 and NOTCH1 Signaling by HIF1α

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    Kit Man Tsang

    2017-09-01

    Full Text Available The generation of functional arterial endothelial cells (aECs from embryonic stem cells (ESCs holds great promise for vascular tissue engineering. However, the mechanisms underlying their generation and the potential of aECs in revascularizing ischemic tissue are not fully understood. Here, we observed that hypoxia exposure of mouse ESCs induced an initial phase of HIF1α-mediated upregulation of the transcription factor Etv2, which in turn induced the commitment to the EC fate. However, sustained activation of HIF1α in these EC progenitors thereafter induced NOTCH1 signaling that promoted the transition to aEC fate. We observed that transplantation of aECs mediated arteriogenesis in the mouse hindlimb ischemia model. Furthermore, transplantation of aECs in mice showed engraftment in ischemic myocardium and restored cardiac function in contrast to ECs derived under normoxia. Thus, HIF1α activation of Etv2 in ESCs followed by NOTCH1 signaling is required for the generation aECs that are capable of arteriogenesis and revascularization of ischemic tissue.

  7. Prox1 regulates the notch1-mediated inhibition of neurogenesis.

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    Valeria Kaltezioti

    2010-12-01

    Full Text Available Activation of Notch1 signaling in neural progenitor cells (NPCs induces self-renewal and inhibits neurogenesis. Upon neuronal differentiation, NPCs overcome this inhibition, express proneural genes to induce Notch ligands, and activate Notch1 in neighboring NPCs. The molecular mechanism that coordinates Notch1 inactivation with initiation of neurogenesis remains elusive. Here, we provide evidence that Prox1, a transcription repressor and downstream target of proneural genes, counteracts Notch1 signaling via direct suppression of Notch1 gene expression. By expression studies in the developing spinal cord of chick and mouse embryo, we showed that Prox1 is limited to neuronal precursors residing between the Notch1+ NPCs and post-mitotic neurons. Physiological levels of Prox1 in this tissue are sufficient to allow binding at Notch1 promoter and they are critical for proper Notch1 transcriptional regulation in vivo. Gain-of-function studies in the chick neural tube and mouse NPCs suggest that Prox1-mediated suppression of Notch1 relieves its inhibition on neurogenesis and allows NPCs to exit the cell cycle and differentiate. Moreover, loss-of-function in the chick neural tube shows that Prox1 is necessary for suppression of Notch1 outside the ventricular zone, inhibition of active Notch signaling, down-regulation of NPC markers, and completion of neuronal differentiation program. Together these data suggest that Prox1 inhibits Notch1 gene expression to control the balance between NPC self-renewal and neuronal differentiation.

  8. Pofut1 point-mutations that disrupt O-fucosyltransferase activity destabilize the protein and abolish Notch1 signaling during mouse somitogenesis.

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    Rieko Ajima

    Full Text Available The segmental pattern of the vertebrate body is established via the periodic formation of somites from the presomitic mesoderm (PSM. This periodical process is controlled by the cyclic and synchronized activation of Notch signaling in the PSM. Protein O-fucosyltransferase1 (Pofut1, which transfers O-fucose to the EGF domains of the Notch1 receptor, is indispensable for Notch signaling activation. The Drosophila homologue Ofut1 was reported to control Notch localization via two different mechanisms, working as a chaperone for Notch or as a regulator of Notch endocytosis. However, these were found to be independent of O-fucosyltransferase activity because the phenotypes were rescued by Ofut1 mutants lacking O-fucosyltransferase activity. Pofut1 may also be involved in the Notch receptor localization in mice. However, the contribution of enzymatic activity of Pofut1 to the Notch receptor dynamics remains to be elucidated. In order to clarify the importance of the O-fucosyltransferase activity of Pofut1 for Notch signaling activation and the protein localization in the PSM, we established mice carrying point mutations at the 245th a.a. or 370-372th a.a., highly conserved amino-acid sequences whose mutations disrupt the O-fucosyltransferase activity of both Drosophila Ofut1 and mammalian Pofut1, with the CRISPR/Cas9 mediated genome-engineering technique. Both mutants displayed the same severely perturbed somite formation and Notch1 subcellular localization defects as the Pofut1 null mutants. In the mutants, Pofut1 protein, but not RNA, became undetectable by E9.5. Furthermore, both wild-type and mutant Pofut1 proteins were degraded through lysosome dependent machinery. Pofut1 protein loss in the point mutant embryos caused the same phenotypes as those observed in Pofut1 null embryos.

  9. Melatonin rescues cardiac thioredoxin system during ischemia-reperfusion injury in acute hyperglycemic state by restoring Notch1/Hes1/Akt signaling in a membrane receptor-dependent manner.

    Science.gov (United States)

    Yu, Liming; Fan, Chongxi; Li, Zhi; Zhang, Jian; Xue, Xiaodong; Xu, Yinli; Zhao, Guolong; Yang, Yang; Wang, Huishan

    2017-01-01

    Stress hyperglycemia is commonly observed in patients suffering from ischemic heart disease. It not only worsens cardiovascular prognosis but also attenuates the efficacies of various cardioprotective agents. This study aimed to investigate the protective effect of melatonin against myocardial ischemia-reperfusion (MI/R) injury in acute hyperglycemic state with a focus on Notch1/Hes1/Akt signaling and intracellular thioredoxin (Trx) system. Sprague Dawley rats were subjected to MI/R surgery and high-glucose (HG, 500 g/L) infusion (4 mL/kg/h) to induce temporary hyperglycemia. Rats were treated with or without melatonin (10 mg/kg/d) during the operation. Furthermore, HG (33 mmol/L)-incubated H9c2 cardiomyoblasts were treated in the presence or absence of luzindole (a competitive melatonin receptor antagonist), DAPT (a γ-secretase inhibitor), LY294002 (a PI3-kinase/Akt inhibitor), or thioredoxin-interacting protein (Txnip) adenoviral vectors. We found that acute hyperglycemia aggravated MI/R injury by suppressing Notch1/Hes1/Akt signaling and intracellular Trx activity. Melatonin treatment effectively ameliorated MI/R injury by reducing infarct size, myocardial apoptosis, and oxidative stress. Moreover, melatonin also markedly enhanced Notch1/Hes1/Akt signaling and rescued intracellular Trx system by upregulating Notch1, N1ICD, Hes1, and p-Akt expressions, increasing Trx activity, and downregulating Txnip expression. However, these effects were blunted by luzindole, DAPT, or LY294002. Additionally, Txnip overexpression not only decreased Trx activity, but also attenuated the cytoprotective effect of melatonin. We conclude that impaired Notch1 signaling aggravates MI/R injury in acute hyperglycemic state. Melatonin rescues Trx system by reducing Txnip expression via Notch1/Hes1/Akt signaling in a membrane receptor-dependent manner. Its role as a prophylactic/therapeutic drug deserves further clinical study. © 2016 John Wiley & Sons A/S. Published by John Wiley

  10. Rho/ROCK-dependent inhibition of 3T3-L1 adipogenesis by G-protein-deamidating dermonecrotic toxins: differential regulation of Notch1, Pref1/Dlk1, and β-catenin signaling

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    Yuka eBannai

    2012-06-01

    Full Text Available The dermonecrotic toxins from Pasteurella multocida (PMT, Bordetella (DNT, Escherichia coli (CNF1-3 and Yersinia (CNFY modulate their G-protein targets through deamidation and/or transglutamination of an active site Gln residue, which results in activation of the G protein and its cognate downstream signaling pathways. Whereas DNT and the CNFs act on small Rho GTPases, PMT acts on the α subunit of heterotrimeric Gq, Gi and G12/13 proteins. We previously demonstrated that PMT potently blocks adipogenesis and adipocyte differentiation in a calcineurin-independent manner through downregulation of Notch1 and stabilization of β-catenin and Pref1/Dlk1, key proteins in signaling pathways strongly linked to cell fate decisions, including fat and bone development. Here, we report that similar to PMT, DNT and CNF1 completely block adipogenesis and adipocyte differentiation by preventing upregulation of adipocyte markers, PPARγ and C/EBPα, while stabilizing the expression of Pref1/Dlk1 and β-catenin. We show that the Rho/ROCK inhibitor Y-27632 prevented or reversed these toxin-mediated effects, strongly supporting a role for Rho/ROCK signaling in dermonecrotic toxin-mediated inhibition of adipogenesis and adipocyte differentiation. Toxin treatment was also accompanied by downregulation of Notch1 expression, although this inhibition was independent of Rho/ROCK signaling. We further show that PMT-mediated downregulation of Notch1 expression occurs primarily through G12/13 signaling. Our results reveal new details of the pathways involved in dermonecrotic toxin action on adipocyte differentiation, and the role of Rho/ROCK signaling in mediating toxin effects on Wnt/β-catenin and Notch1 signaling, and in particular the role of Gq and G12/13 in mediating PMT effects on Rho/ROCK and Notch1 signaling.

  11. Notch1 and 4 Signaling Responds to an Increasing Vascular Wall Shear Stress in a Rat Model of Arteriovenous Malformations

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    Jian Tu

    2014-01-01

    Full Text Available Notch signaling is suggested to promote the development and maintenance of cerebral arteriovenous malformations (AVMs, and an increasing wall shear stress (WSS contributes to AVM rupture. Little is known about whether WSS impacts Notch signaling, which is important for understanding the angiogenesis of AVMs. WSS was measured in arteriovenous fistulas (AVF surgically created in 96 rats at different time points over a period of 84 days. The expression of Notch receptors 1 and 4 and their ligands, Delta1 and 4, Jagged1, and Notch downstream gene target Hes1 was quantified in “nidus” vessels. The interaction events between Notch receptors and their ligands were quantified using proximity ligation assay. There was a positive correlation between WSS and time (r=0.97; P<0.001. The expression of Notch receptors and their ligands was upregulated following AVF formation. There was a positive correlation between time and the number of interactions between Notch receptors and their ligands aftre AVF formation (r=0.62, P<0.05 and a positive correlation between WSS and the number of interactions between Notch receptors and their ligands (r=0.87, P<0.005. In conclusion, an increasing WSS may contribute to the angiogenesis of AVMs by activation of Notch signaling.

  12. Notch1 mutations are drivers of oral tumorigenesis

    Science.gov (United States)

    Jones, Sian; Brait, Mariana; Agrawal, Nishant; Koch, Wayne; McCord, Christine L.; Riley, David R.; Angiuoli, Samuel V.; Velculescu, Victor E.; Jiang, Wei-Wen; Sidransky, David

    2014-01-01

    Disruption of NOTCH1 signaling was recently discovered in head and neck cancer. This study aims to evaluate NOTCH1 alterations in the progression of oral squamous cell carcinoma (OSCC) and compare the occurrence of these mutations in Chinese and Caucasian populations. We used a high-throughput-PCR-based enrichment technology and next generation sequencing (NGS) to sequence NOTCH1 in 144 samples collected in China. Forty nine samples were normal oral mucosa from patients undergoing oral surgery, 45 were oral leukoplakia biopsies and 50 were chemoradiation naïve OSCC samples with 22 paired-normal tissues from the adjacent unaffected areas. NOTCH1 mutations were found in 54% of primary OSCC and 60% of pre-malignant lesions. Importantly, almost 60% of leukoplakia patients with mutated NOTCH1 carried mutations that were also identified in OSCC, indicating an important role of these clonal events in the progression of early neoplasms. We then compared all known NOTCH1 mutations identified in Chinese OSCC patients with those reported in Caucasians to date. Although we found obvious overlaps in critical regulatory NOTCH1 domains alterations and identified specific mutations shared by both groups, possible gain-of-function mutations were predominantly seen in Chinese population. Our findings demonstrate that pre-malignant lesions display NOTCH1 mutations at an early stage and are thus bona fide drivers of OSCC progression. Moreover, our results reveal that NOTCH1 promotes distinct tumorigenic mechanisms in patients from different ethnical populations. PMID:25406187

  13. Notch 1 impairs osteoblastic cell differentiation.

    Science.gov (United States)

    Sciaudone, Maria; Gazzerro, Elisabetta; Priest, Leah; Delany, Anne M; Canalis, Ernesto

    2003-12-01

    Notch receptors are single pass transmembrane receptors activated by membrane-bound ligands with a role in cell proliferation and differentiation. As Notch 1 and 2 mRNAs are expressed by osteoblasts and induced by cortisol, we postulated that Notch could regulate osteoblastogenesis. We investigated the effects of retroviral vectors directing the constitutive expression of the Notch 1 intracellular domain (NotchIC) in murine ST-2 stromal and in MC3T3 cells. NotchIC overexpression was documented by increased Notch 1 transcripts and activity of the Notch-dependent Hairy Enhancer of Split promoter. In the presence of bone morphogenetic protein-2 (BMP-2), ST-2 cells differentiated toward osteoblasts forming mineralized nodules, and Notch 1 opposed this effect and decreased the expression of osteocalcin, type I collagen, and alkaline phosphatase transcripts and Delta2Delta FosB protein. Further, NotchIC decreased Wnt/beta-catenin signaling. As cells differentiated in the presence of BMP-2, they underwent apoptosis, and Notch opposed this event. In the presence of cortisol, NotchIC induced the formation of mature adipocytes and enhanced the effect of cortisol on adipsin, peroxisome proliferator-activated receptor-gamma2 and CCAAT enhancer binding protein alpha and delta mRNA levels. NotchIC also opposed MC3T3 cell differentiation and the expression of a mature osteoblastic phenotype. In conclusion, NotchIC impairs osteoblast differentiation and enhances adipogenesis in stromal cell cultures.

  14. Redundant Notch1 and Notch2 signaling is necessary for IFNγ secretion by T helper 1 cells during infection with Leishmania major.

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    Floriane Auderset

    Full Text Available The protective immune response to intracellular parasites involves in most cases the differentiation of IFNγ-secreting CD4(+ T helper (Th 1 cells. Notch receptors regulate cell differentiation during development but their implication in the polarization of peripheral CD4(+ T helper 1 cells is not well understood. Of the four Notch receptors, only Notch1 (N1 and Notch2 (N2 are expressed on activated CD4(+ T cells. To investigate the role of Notch in Th1 cell differentiation following parasite infection, mice with T cell-specific gene ablation of N1, N2 or both (N1N2(ΔCD4Cre were infected with the protozoan parasite Leishmania major. N1N2(ΔCD4Cre mice, on the C57BL/6 L. major-resistant genetic background, developed unhealing lesions and uncontrolled parasitemia. Susceptibility correlated with impaired secretion of IFNγ by draining lymph node CD4(+ T cells and increased secretion of the IL-5 and IL-13 Th2 cytokines. Mice with single inactivation of N1 or N2 in their T cells were resistant to infection and developed a protective Th1 immune response, showing that CD4(+ T cell expression of N1 or N2 is redundant in driving Th1 differentiation. Furthermore, we show that Notch signaling is required for the secretion of IFNγ by Th1 cells. This effect is independent of CSL/RBP-Jκ, the major effector of Notch receptors, since L. major-infected mice with a RBP-Jκ deletion in their T cells were able to develop IFNγ-secreting Th1 cells, kill parasites and heal their lesions. Collectively, we demonstrate here a crucial role for RBP-Jκ-independent Notch signaling in the differentiation of a functional Th1 immune response following L. major infection.

  15. Proliferation, cell cycle exit, and onset of terminal differentiation in cultured keratinocytes: pre-programmed pathways in control of C-Myc and Notch1 prevail over extracellular calcium signals.

    Science.gov (United States)

    Kolly, Carine; Suter, Maja M; Müller, Eliane J

    2005-05-01

    So far it was reported that a switch from low to high extracellular calcium induces growth arrest and terminal differentiation in cultured human and mouse keratinocytes. We had observed that both canine and mouse keratinocytes proliferate in high (1.8 mM, respectively, 1.2 mM) or low (0.09 and 0.06 mM) calcium-containing medium. In-depth analysis of this phenomenon revealed, as reported here, that the switch between proliferation and terminal differentiation occurred irrespective of calcium conditions when the canine and murine keratinocytes reach confluency. The "confluency switch" coincided with transcriptional upregulation of cell cycle inhibitors p21(WAF1) and p27(KIP1) as well as proteins marking onset of terminal differentiation. It was further accompanied by downregulation and nuclear clearance of c-Myc, and conversely activation of Notch1, which are shown to be critical determinants of this process. Together, this study demonstrates that even in the absence of and similar to their in vivo environment, cultured canine and mouse keratinocytes follow a pre-defined differentiation program. This program is in control of c-Myc and Notch1 and does not require complementary signals for onset of terminal differentiation except those given by cell-cell contact. Once triggered, completion of the terminal differentiation process depends on elevated extracellular calcium to stabilize intercellular junctions and components of the cornified envelope.

  16. Chemotherapeutic treatment is associated with Notch1 induction in cutaneous T-cell lymphoma

    DEFF Research Database (Denmark)

    Kamstrup, Maria R; Biskup, Edyta; Manfè, Valentina

    2017-01-01

    The Notch pathway is important for survival of cutaneous T-cell lymphoma (CTCL) cells. We investigated the effect of chemotherapy (doxorubicin, etoposide, and gemcitabine) and radiation modalities on Notch signaling in CTCL cell lines. Chemotherapy induced Notch1 expression at the mRNA and protein...... level in MyLa2000 and Hut78. Upregulation of well-established Notch targets supported the functional activity of Notch1. Transfection of Notch1 siRNA into MyLa2000 cells was not able to suppress the effects of chemotherapy on Notch1 activation significantly. Notch1 knockdown in combination...... with doxorubicin, etoposide, or gemcitabine compared to chemotherapy alone decreased cell viability by 12, 20, and 26%, respectively (p MyLa2000 but not SeAx) and psoralen plus UVA (PUVA) (in MyLa2000, Hut78, and SeAx) increased the expression of Notch1 family members. Our results...

  17. Periostin associates with Notch1 precursor to maintain Notch1 expression under a stress condition in mouse cells.

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    Hideyuki Tanabe

    Full Text Available BACKGROUND: Matricellular proteins, including periostin, modulate cell-matrix interactions and cell functions by acting outside of cells. METHODS AND FINDINGS: In this study, however, we reported that periostin physically associates with the Notch1 precursor at its EGF repeats in the inside of cells. Moreover, by using the periodontal ligament of molar from periostin-deficient adult mice (Pn-/- molar PDL, which is a constitutively mechanically stressed tissue, we found that periostin maintained the site-1 cleaved 120-kDa transmembrane domain of Notch1 (N1 level without regulating Notch1 mRNA expression. N1 maintenance in vitro was also observed under such a stress condition as heat and H(2O(2 treatment in periostin overexpressed cells. Furthermore, we found that the expression of a downstream effector of Notch signaling, Bcl-xL was decreased in the Pn-/- molar PDL, and in the molar movement, cell death was enhanced in the pressure side of Pn-/- molar PDL. CONCLUSION: These results suggest the possibility that periostin inhibits cell death through up-regulation of Bcl-xL expression by maintaining the Notch1 protein level under the stress condition, which is caused by its physical association with the Notch1 precursor.

  18. Retraction: "Down-regulation of Notch-1 and Jagged-1 inhibits prostate cancer cell growth, migration and invasion, and induces apoptosis via inactivation of Akt, mTOR, and NF-κB signaling pathways" by Wang et al.

    Science.gov (United States)

    2016-08-01

    The above article, published online on January 5, 2010 in Wiley Online Library (wileyonlinelibrary.com), has been retracted by agreement between the journal Editor in Chief, Gary S. Stein, and Wiley Periodicals, Inc. The retraction has been agreed following an investigation from Wayne State University involving the first author and the corresponding author that found Figure 5A to be inappropriately manipulated. REFERENCE Wang Z, Li Y, Banerjee S, Kong D, Ahmad A, Nogueira V, Hay N, Sarkar FH. 2010. Down-regulation of Notch-1 and Jagged-1 inhibits prostate cancer cell growth, migration and invasion, and induces apoptosis via inactivation of Akt, mTOR, and NF-κB signaling pathways. J Cell Biochem 109:726-736; doi: 10.1002/jcb.22451. © 2016 Wiley Periodicals, Inc.

  19. Inhibitory role of Notch1 in calcific aortic valve disease.

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    Asha Acharya

    Full Text Available Aortic valve calcification is the most common form of valvular heart disease, but the mechanisms of calcific aortic valve disease (CAVD are unknown. NOTCH1 mutations are associated with aortic valve malformations and adult-onset calcification in families with inherited disease. The Notch signaling pathway is critical for multiple cell differentiation processes, but its role in the development of CAVD is not well understood. The aim of this study was to investigate the molecular changes that occur with inhibition of Notch signaling in the aortic valve. Notch signaling pathway members are expressed in adult aortic valve cusps, and examination of diseased human aortic valves revealed decreased expression of NOTCH1 in areas of calcium deposition. To identify downstream mediators of Notch1, we examined gene expression changes that occur with chemical inhibition of Notch signaling in rat aortic valve interstitial cells (AVICs. We found significant downregulation of Sox9 along with several cartilage-specific genes that were direct targets of the transcription factor, Sox9. Loss of Sox9 expression has been published to be associated with aortic valve calcification. Utilizing an in vitro porcine aortic valve calcification model system, inhibition of Notch activity resulted in accelerated calcification while stimulation of Notch signaling attenuated the calcific process. Finally, the addition of Sox9 was able to prevent the calcification of porcine AVICs that occurs with Notch inhibition. In conclusion, loss of Notch signaling contributes to aortic valve calcification via a Sox9-dependent mechanism.

  20. Notch1 modulates mesenchymal stem cells mediated regulatory T-cell induction.

    Science.gov (United States)

    Del Papa, Beatrice; Sportoletti, Paolo; Cecchini, Debora; Rosati, Emanuela; Balucani, Chiara; Baldoni, Stefano; Fettucciari, Katia; Marconi, Pierfrancesco; Martelli, Massimo F; Falzetti, Franca; Di Ianni, Mauro

    2013-01-01

    Notch1 signaling is involved in regulatory T (Treg)-cell differentiation. We previously demonstrated that, when cocultured with CD3(+) cells, mesenchymal stem cells (MSCs) induced a T-cell population with a regulatory phenotype. Here, we investigated the molecular mechanism underlying MSC induction of human Treg cells. We show that the Notch1 pathway is activated in CD4(+) T cells cocultured with MSCs. Inhibition of Notch1 signaling through GSI-I or the Notch1 neutralizing antibody reduced expression of HES1 (the Notch1 downstream target) and the percentage of MSC-induced CD4(+) CD25(high) FOXP3(+) cells in vitro. Moreover, we demonstrate that FOXP3 is a downstream target of Notch signaling in human cells. No crosstalk between Notch1 and TGF-β signaling pathways was observed in our experimental system. Together, these findings indicate that activation of the Notch1 pathway is a novel mechanism in the human Treg-cell induction mediated by MSCs. © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  1. Notch1 is pan-endothelial at the onset of flow and regulated by flow.

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    Espen D Jahnsen

    Full Text Available Arteriovenous differentiation is a key event during vascular development and hemodynamic forces play an important role. Arteriovenous gene expression is present before the onset of flow, however it remains plastic and flow can alter arteriovenous identity. Notch signaling is especially important in the genetic determination of arteriovenous identity. Nevertheless, the effect of the onset of circulation on Notch expression and signaling has not been studied. The aim of this study is therefore to investigate the interaction of Notch1 signaling and hemodynamic forces during early vascular development. We find that the onset of Notch1 expression coincides with the onset of flow, and that expression is pan-endothelial at the onset of circulation in mouse embryos and only becomes arterial-specific after remodeling has occurred. When we ablate flow in the early embryo, endothelial cells fail to express Notch1. We show that low and disturbed flow patterns upregulate Notch1 expression in endothelial cells in vitro, but that higher shear stress levels do not (≥10 dynes/cm2. Using siRNA, we knocked down Notch1 to investigate the role of Notch1 in mechanotransduction. When we applied shear stress levels similar to those found in embryonic arteries, we found an upregulation of Klf2, Dll1, Dll4, Jag1, Hey1, Nrp1 and CoupTFII but that only Dll4, Hey1, Nrp1 and EphB4 required Notch1 for flow-induced expression. Our results therefore indicate that Notch1 can modulate mechanotransduction but is not a critical mediator of the process since many genes mechanotransduce normally in the absence of Notch1, including genes involved in arteriovenous differentiation.

  2. No evidence for induction of key components of the Notch signaling pathway (Notch-1, Jagged-1) by treatment with UV-B, 1,25(OH)(2)D(3), and/or epigenetic drugs (TSA, 5-Aza) in human keratinocytes in vitro.

    Science.gov (United States)

    Reichrath, Sandra; Reichrath, Jörg

    2012-01-01

    Notch signaling is of high importance for growth and survival of various cell types. We now analyzed the protein expression of two key components of the Notch signaling pathway (Notch-1, Jagged-1) in spontaneously immortalized (HaCaT) and in malignant (SCL-1) human keratinocytes, using western analysis. We found that Notch-1 and its corresponding ligand Jagged-1 are expressed in both cell lines, with no marked change following UV-B treatment. Moreover, treatment of both cell lines before or after UV-B irradiation with 1,25-dihydroxyvitamin D(3), the biologically active form of vitamin D, and/or epigenetic modulating drugs (TSA; 5-Aza) did not result in a marked modulation of the protein expression of Notch-1 or Jagged-1. Under the experimental conditions of this study, treatment with 1,25(OH)(2)D(3) protected human keratinocytes in part against the antiproliferative effects of UV-B-radiation. In conclusion, our findings do not point at a differential expression of these two key components of Notch signaling in non-malignant as compared to malignant human keratinocytes, indicating that alterations in their expression are not of importance for the photocarcinogenesis of human squamous cell carcinomas. Moreover, our findings do not support the hypothesis that modulation of Notch signaling may be involved in the photoprotective effect of 1,25-dihydroxyvitamin D(3), that we and others reported previously. Additionally, we demonstrate that epigenetic modulating drugs (TSA, 5-Aza) do not markedly modulate the expression Notch-1 or Jagged-1 in UV-B-treated human keratinocytes in vitro.

  3. CYFIP1 is directly controlled by NOTCH1 and down-regulated in cutaneous squamous cell carcinoma.

    Science.gov (United States)

    Dziunycz, Piotr J; Neu, Johannes; Lefort, Karine; Djerbi, Nadia; Freiberger, Sandra N; Iotzova-Weiss, Guergana; French, Lars E; Dotto, Gian-Paolo; Hofbauer, Günther F

    2017-01-01

    Squamous cell carcinoma of the skin (SCC) represents one of the most common cancers in the general population and is associated with a substantial risk of metastasis. Previous work uncovered the functional role of CYFIP1 in epithelial tumors as an invasion inhibitor. It was down-regulated in some cancers and correlated with the metastatic properties of these malignant cells. We investigated its role and expression mechanisms in SCC. We analyzed the expression of CYFIP1 in patient derived SCC, primary keratinocytes and SCC cell lines, and correlated it to the differentiation and NOTCH1 levels. We analyzed the effects of Notch1 manipulation on CYFIP1 expression and confirmed the biding of Notch1 to the CYFIP1 promoter. CYFIP1 expression was down-regulated in SCC and correlated inversely with histological differentiation of tumors. As keratinocyte differentiation depends on Notch1 signaling, we investigated the influence of Notch1 on CYFIP1 expression. CYFIP1 mRNA was highly increased in human Notch1-overexpressing keratinocytes. Further manipulation of the Notch1 pathway in keratinocytes impacted CYFIP1 levels and chromatin immunoprecipitation assay confirmed the direct binding of Notch1 to the CYFIP1 promoter. CYFIP1 may be a link between loss of differentiation and invasive potential in malignant keratinocytes of cutaneous squamous cell carcinoma.

  4. CYFIP1 is directly controlled by NOTCH1 and down-regulated in cutaneous squamous cell carcinoma.

    Directory of Open Access Journals (Sweden)

    Piotr J Dziunycz

    Full Text Available Squamous cell carcinoma of the skin (SCC represents one of the most common cancers in the general population and is associated with a substantial risk of metastasis. Previous work uncovered the functional role of CYFIP1 in epithelial tumors as an invasion inhibitor. It was down-regulated in some cancers and correlated with the metastatic properties of these malignant cells. We investigated its role and expression mechanisms in SCC. We analyzed the expression of CYFIP1 in patient derived SCC, primary keratinocytes and SCC cell lines, and correlated it to the differentiation and NOTCH1 levels. We analyzed the effects of Notch1 manipulation on CYFIP1 expression and confirmed the biding of Notch1 to the CYFIP1 promoter. CYFIP1 expression was down-regulated in SCC and correlated inversely with histological differentiation of tumors. As keratinocyte differentiation depends on Notch1 signaling, we investigated the influence of Notch1 on CYFIP1 expression. CYFIP1 mRNA was highly increased in human Notch1-overexpressing keratinocytes. Further manipulation of the Notch1 pathway in keratinocytes impacted CYFIP1 levels and chromatin immunoprecipitation assay confirmed the direct binding of Notch1 to the CYFIP1 promoter. CYFIP1 may be a link between loss of differentiation and invasive potential in malignant keratinocytes of cutaneous squamous cell carcinoma.

  5. Epidermal Notch1 recruits RORγ + group 3 innate lymphoid cells to orchestrate normal skin repair

    NARCIS (Netherlands)

    Z. Li (Zhi); T. Hodgkinson (Tom); E.J. Gothard (Elizabeth J.); S. Boroumand (Soulmaz); R. Lamb (Rebecca); I. Cummins (Ian); P. Narang (Priyanka); A. Sawtell (Amy); J. Coles (Jenny); G. Leonov (German); A. Reboldi (Andrea); C.D. Buckley; T. Cupedo (Tom); C. Siebel (Christian); A. Bayat (Ardeshir); M. Coles (Mark); C.A. Ambler (Carrie A.)

    2016-01-01

    textabstractNotch has a well-defined role in controlling cell fate decisions in the embryo and the adult epidermis and immune systems, yet emerging evidence suggests Notch also directs non-cell-autonomous signalling in adult tissues. Here, we show that Notch1 works as a damage response signal.

  6. Notch1 activity in the olfactory bulb is odour-dependent and contributes to olfactory behaviour.

    Science.gov (United States)

    Brai, Emanuele; Marathe, Swananda; Zentilin, Lorena; Giacca, Mauro; Nimpf, Johannes; Kretz, Robert; Scotti, Alessandra; Alberi, Lavinia

    2014-11-01

    Notch signalling plays an important role in synaptic plasticity, learning and memory functions in both Drosophila and rodents. In this paper, we report that this feature is not restricted to hippocampal networks but also involves the olfactory bulb (OB). Odour discrimination and olfactory learning in rodents are essential for survival. Notch1 expression is enriched in mitral cells of the mouse OB. These principal neurons are responsive to specific input odorants and relay the signal to the olfactory cortex. Olfactory stimulation activates a subset of mitral cells, which show an increase in Notch activity. In Notch1cKOKln mice, the loss of Notch1 in mitral cells affects the magnitude of the neuronal response to olfactory stimuli. In addition, Notch1cKOKln mice display reduced olfactory aversion to propionic acid as compared to wildtype controls. This indicates, for the first time, that Notch1 is involved in olfactory processing and may contribute to olfactory behaviour. © 2014 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

  7. Associations between polymorphisms in the NICD domain of bovine NOTCH1 gene and growth traits in Chinese Qinchuan cattle.

    Science.gov (United States)

    Liu, Mei; Zhang, Chenge; Lai, Xinsheng; Xue, Jing; Lan, Xianyong; Lei, Chuzhao; Jia, Yutang; Chen, Hong

    2017-05-01

    NOTCH1 is one of the four mammalian Notch receptors, which is involved in the Notch signaling pathway. Specifically, NOTCH1 promotes the proliferation of myogenic precursor cells, and the NICD domain of NOTCH1 can impair regeneration of skeletal muscles. However, similar research on the bovine NOTCH1 gene is lacking. In this study, we detected the polymorphisms of the bovine NOTCH1 gene in a total of 448 individuals from Chinese Qinchuan cattle with DNA pooling, forced PCR-RFLP, and DNA sequencing methods. Five novel SNPs were identified within the NICD domain, and eight haplotypes comprising combinations of these five SNPs were studied as well. The association analysis of SNPs' effects with growth traits revealed that g.A48250G was significantly associated with body height, body weight, and height at hip cross, and that g.A49239C only showed significant associations with body height. This suggests that the NOTCH1 gene is a strong candidate gene that could be utilized as a promising marker in beef cattle breeding programs.

  8. HIGHLY CONSERVED O-FUCOSE SITES HAVE DISTINCT EFFECTS ON NOTCH1 FUNCTION

    Science.gov (United States)

    Rampal, Raajit; Arboleda-Velasquez, Joseph F.; Nita-Lazar, Alexandra; Kosik, Kenneth S.; Haltiwanger, Robert S.

    2005-01-01

    The extracellular domain of mouse Notch1 contains 36 tandem epidermal growth factor like (EGF) repeats, many of which are modified with O-fucose. Previous work from several laboratories has indicated that O-fucosylation plays an important role in ligand mediated Notch activation. Nonetheless, it is not clear whether all, or a subset, of the EGF repeats need to be O-fucosylated. Three O-fucose sites are invariantly conserved in all Notch homologues with 36 EGF repeats (within EGF repeats 12, 26 and 27). In order to investigate which O-fucose sites on Notch1 are important for ligand-mediated signaling, we mutated the three invariant O-fucose sites in mouse Notch1, along with several less highly conserved sites, and evaluated their ability to transduce Jagged1 and Delta1 mediated signaling in a cell-based assay. Our analysis revealed that mutation of any of the three invariant O-fucose sites resulted in significant changes in both Delta1 and Jagged1 mediated signaling, but mutations in less highly conserved sites had no detectable effect. Interestingly, mutation of each invariant site gave a distinct effect on Notch function. Mutation of the O-fucose site in EGF repeat 12 resulted in loss of Delta1 and Jagged1 signaling, while mutation of the O-fucose site in EGF repeat 26 resulted in hyperactivation of both Delta1 and Jagged1 signaling. Mutation of the O-fucose site in EGF repeat 27 resulted in faulty trafficking of the Notch receptor to the cell surface and a decreased S1 processing of the receptor. These results indicate that the most highly conserved O-fucose sites in Notch1 are important for both processing and ligand mediated signaling in the context of a cell-based signaling assay. PMID:15994302

  9. NOTCH1 and NOTCH2 regulate epithelial cell proliferation in mouse and human gastric corpus.

    Science.gov (United States)

    Demitrack, Elise S; Gifford, Gail B; Keeley, Theresa M; Horita, Nobukatsu; Todisco, Andrea; Turgeon, D Kim; Siebel, Christian W; Samuelson, Linda C

    2017-02-01

    The Notch signaling pathway is known to regulate stem cells and epithelial cell homeostasis in gastrointestinal tissues; however, Notch function in the corpus region of the stomach is poorly understood. In this study we examined the consequences of Notch inhibition and activation on cellular proliferation and differentiation and defined the specific Notch receptors functioning in the mouse and human corpus. Notch pathway activity was observed in the mouse corpus epithelium, and gene expression analysis revealed NOTCH1 and NOTCH2 to be the predominant Notch receptors in both mouse and human. Global Notch inhibition for 5 days reduced progenitor cell proliferation in the mouse corpus, as well as in organoids derived from mouse and human corpus tissue. Proliferation effects were mediated through both NOTCH1 and NOTCH2 receptors, as demonstrated by targeting each receptor alone or in combination with Notch receptor inhibitory antibodies. Analysis of differentiation by marker expression showed no change to the major cell lineages; however, there was a modest increase in the number of transitional cells coexpressing markers of mucous neck and chief cells. In contrast to reduced proliferation after pathway inhibition, Notch activation in the adult stomach resulted in increased proliferation coupled with reduced differentiation. These findings suggest that NOTCH1 and NOTCH2 signaling promotes progenitor cell proliferation in the mouse and human gastric corpus, which is consistent with previously defined roles for Notch in promoting stem and progenitor cell proliferation in the intestine and antral stomach. Here we demonstrate that the Notch signaling pathway is essential for proliferation of stem cells in the mouse and human gastric corpus. We identify NOTCH1 and NOTCH2 as the predominant Notch receptors expressed in both mouse and human corpus and show that both receptors are required for corpus stem cell proliferation. We show that chronic Notch activation in corpus stem

  10. Constitutively active Notch1 converts cranial neural crest-derived frontonasal mesenchyme to perivascular cells in vivo

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    Sophie R. Miller

    2017-03-01

    Full Text Available Perivascular/mural cells originate from either the mesoderm or the cranial neural crest. Regardless of their origin, Notch signalling is necessary for their formation. Furthermore, in both chicken and mouse, constitutive Notch1 activation (via expression of the Notch1 intracellular domain is sufficient in vivo to convert trunk mesoderm-derived somite cells to perivascular cells, at the expense of skeletal muscle. In experiments originally designed to investigate the effect of premature Notch1 activation on the development of neural crest-derived olfactory ensheathing glial cells (OECs, we used in ovo electroporation to insert a tetracycline-inducible NotchΔE construct (encoding a constitutively active mutant of mouse Notch1 into the genome of chicken cranial neural crest cell precursors, and activated NotchΔE expression by doxycycline injection at embryonic day 4. NotchΔE-targeted cells formed perivascular cells within the frontonasal mesenchyme, and expressed a perivascular marker on the olfactory nerve. Hence, constitutively activating Notch1 is sufficient in vivo to drive not only somite cells, but also neural crest-derived frontonasal mesenchyme and perhaps developing OECs, to a perivascular cell fate. These results also highlight the plasticity of neural crest-derived mesenchyme and glia.

  11. Mutations in NOTCH1 PEST domain orchestrate CCL19-driven homing of chronic lymphocytic leukemia cells by modulating the tumor suppressor gene DUSP22.

    Science.gov (United States)

    Arruga, F; Gizdic, B; Bologna, C; Cignetto, S; Buonincontri, R; Serra, S; Vaisitti, T; Gizzi, K; Vitale, N; Garaffo, G; Mereu, E; Diop, F; Neri, F; Incarnato, D; Coscia, M; Allan, J; Piva, R; Oliviero, S; Furman, R R; Rossi, D; Gaidano, G; Deaglio, S

    2017-09-01

    Even if NOTCH1 is commonly mutated in chronic lymphocytic leukemia (CLL), its functional impact in the disease remains unclear. Using CRISPR/Cas9-generated Mec-1 cell line models, we show that NOTCH1 regulates growth and homing of CLL cells by dictating expression levels of the tumor suppressor gene DUSP22. Specifically, NOTCH1 affects the methylation of DUSP22 promoter by modulating a nuclear complex, which tunes the activity of DNA methyltransferase 3A (DNMT3A). These effects are enhanced by PEST-domain mutations, which stabilize the molecule and prolong signaling. CLL patients with a NOTCH1-mutated clone showed low levels of DUSP22 and active chemotaxis to CCL19. Lastly, in xenograft models, NOTCH1-mutated cells displayed a unique homing behavior, localizing preferentially to the spleen and brain. These findings connect NOTCH1, DUSP22, and CCL19-driven chemotaxis within a single functional network, suggesting that modulation of the homing process may provide a relevant contribution to the unfavorable prognosis associated with NOTCH1 mutations in CLL.

  12. Normalization of vibration signals generated under highly varying speed and load with application to signal separation

    Science.gov (United States)

    Urbanek, Jacek; Barszcz, Tomasz; Strączkiewicz, Marcin; Jablonski, Adam

    2017-01-01

    The paper presents a normalization dedicated to transform non-stationary vibration signals into signals characterized by purely stationary properties. For this purpose, a novel class of generalized periodic signals is defined followed by a proposition of a normalization technique, which takes advantage of available, instantaneous values of operational parameters. Within the paper, a well-known discrete-random separation (DRS) technique is recalled as an exemplary technique, which has been restricted to stationary signals so far. The authors present a step-by-step adoption of the DRS to non-stationary signals. The method is applied to simulated signal, test rig signal, and a vibration signal from industrial object. Additionally, for the purpose of synthesis of simulated signal, a new model of multi-component vibrations generated under varying regime is proposed. The presented method aims to expand existing solutions dealing with varying frequency to a more general solution dealing with independent, simultaneous varying frequency and amplitude of signal components.

  13. Involvement of Notch1 inhibition in serum-stimulated glia and oligodendrocyte differentiation from human mesenchymal stem cells

    Directory of Open Access Journals (Sweden)

    Yi-Jang Lee

    2010-11-01

    Full Text Available Yi-Jang Lee1, Shih-Chieh Hung2–5, Mien-Sheng Chu41Department of Biomedical Imaging and Radiological Sciences, 2Institute of Clinical Medicine, 3Institute of Pharmacology, Faculty of Medicine, National Yang-Ming University, Taipei, Taiwan; 4Stem Cell Laboratory, Department of Medical Research and Education, 5Department of Orthopedics, Taipei Veterans General Hospital, Taipei 112, TaiwanAbstract: The use of in vitro oligodendrocyte differentiation for transplantation of stem cells to treat demyelinating diseases is an important consideration. In this study, we investigated the effects of serum on glia and oligodendrocyte differentiation from human mesenchymal stem cells (KP-hMSCs. We found that serum deprivation resulted in a reversible downregulation of glial- and oligodendrocyte-specific markers. Serum stimulated expression of oligodendrocyte markers, such as galactocerebroside, as well as Notch1 and JAK1 transcripts. Inhibition of Notch1 activation by the Notch inhibitor, MG132, led to enhanced expression of a serum-stimulated oligodendrocyte marker. This marker was undetectable in serum-deprived KP-hMSCs treated with MG132, suggesting that inhibition of Notch1 function is additive to serum-stimulated oligodendrocyte differentiation. Furthermore, a dominant-negative mutant RBP-J protein also inhibited Notch1 function and led to upregulation of oligodendrocyte-specific markers. Our results demonstrate that serum-stimulated oligodendrocyte differentiation is enhanced by the inhibition of Notch1-associated functions.Keywords: mesenchymal stem cells, glia and oligodendrocyte differentiation, Notch1 signaling, serum deprivation

  14. NOTCH1 Inhibits Activation of ATM by Impairing the Formation of an ATM-FOXO3a-KAT5/Tip60 Complex.

    Science.gov (United States)

    Adamowicz, Marek; Vermezovic, Jelena; d'Adda di Fagagna, Fabrizio

    2016-08-23

    The DNA damage response (DDR) signal transduction pathway is responsible for sensing DNA damage and further relaying this signal into the cell. ATM is an apical DDR kinase that orchestrates the activation and the recruitment of downstream DDR factors to induce cell-cycle arrest and repair. We have previously shown that NOTCH1 inhibits ATM activation upon DNA damage, but the underlying mechanism remains unclear. Here, we show that NOTCH1 does not impair ATM recruitment to DNA double-strand breaks (DSBs). Rather, NOTCH1 prevents binding of FOXO3a and KAT5/Tip60 to ATM through a mechanism in which NOTCH1 competes with FOXO3a for ATM binding. Lack of FOXO3a binding to ATM leads to the loss of KAT5/Tip60 association with ATM. Moreover, expression of NOTCH1 or depletion of ATM impairs the formation of the FOXO3a-KAT5/Tip60 protein complex. Finally, we show that pharmacological induction of FOXO3a nuclear localization sensitizes NOTCH1-driven cancers to DNA-damage-induced cell death. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

  15. The γ-secretase inhibitor PF-03084014 combined with fludarabine antagonizes migration, invasion and angiogenesis in NOTCH1-mutated CLL cells.

    Science.gov (United States)

    López-Guerra, M; Xargay-Torrent, S; Rosich, L; Montraveta, A; Roldán, J; Matas-Céspedes, A; Villamor, N; Aymerich, M; López-Otín, C; Pérez-Galán, P; Roué, G; Campo, E; Colomer, D

    2015-01-01

    Targeting Notch signaling has emerged as a promising therapeutic strategy for chronic lymphocytic leukemia (CLL), especially for the poor prognostic subgroup of NOTCH1-mutated patients. Here, we report that the γ-secretase inhibitor PF-03084014 inhibits the constitutive Notch activation and induces selective apoptosis in CLL cells carrying NOTCH1 mutations. Combination of PF-03084014 with fludarabine has a synergistic antileukemic effect in primary NOTCH1-mutated CLL cells, even in the presence of the protective stroma. At transcriptional level, PF-03084014 plus fludarabine treatment induces the upregulation of the proapoptotic gene HRK and the downmodulation of MMP9, IL32 and RAC2 genes that are related to invasion and chemotaxis. PF-03084014 also overcomes fludarabine-mediated activation of nuclear factor-κB signaling. Moreover, this combination impairs angiogenesis and CXCL12-induced responses in NOTCH1-mutated CLL cells, in particular those related to tumoral migration and invasion. Importantly, all these collaborative effects are specific for NOTCH1 mutation and do not occur in unmutated cases. In conclusion, we provide evidence that Notch is a therapeutic target in CLL cases with NOTCH1-activating mutations, supporting the use of Notch pathway inhibitors in combination with chemotherapy as a promising approach for the treatment of these high-risk CLL patients.

  16. Activation of Notch1 inhibits medial edge epithelium apoptosis in all-trans retinoic acid-induced cleft palate in mice

    Energy Technology Data Exchange (ETDEWEB)

    Zhang, Yadong; Dong, Shiyi; Wang, Weicai; Wang, Jianning [Department of Oral and Maxillofacial Surgery, Guanghua School of Stomatology, Hospital of Stomatology, Sun Yat-sen University, Guangzhou, Guangdong 510055 (China); Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-sen University, Guangzhou, Guangdong 510055 (China); Wang, Miao [Department of Oral and Maxillofacial Surgery, Kiang Wu Hospital, Macao (China); Chen, Mu [Department of Stomatology, Nanshan Affiliated Hospital of Guangdong Medical College, Shenzhen (China); Hou, Jinsong [Department of Oral and Maxillofacial Surgery, Guanghua School of Stomatology, Hospital of Stomatology, Sun Yat-sen University, Guangzhou, Guangdong 510055 (China); Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-sen University, Guangzhou, Guangdong 510055 (China); Huang, Hongzhang, E-mail: drhuang52@163.com [Department of Oral and Maxillofacial Surgery, Guanghua School of Stomatology, Hospital of Stomatology, Sun Yat-sen University, Guangzhou, Guangdong 510055 (China); Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-sen University, Guangzhou, Guangdong 510055 (China)

    2016-08-26

    Administration of all-trans retinoic acid (atRA) on E12.0 (embryonic day 12.0) leads to failure of medial edge epithelium (MEE) disappearance and cleft palate. However, the molecular mechanism underlying the relationship between atRA and MEE remains to be identified. In this study, atRA (200 mg/kg) administered by gavage induced a 75% incidence of cleft palate in C57BL/6 mice. Notch1 was up-regulated in MEE cells in the atRA-treated group compared with the controls at E15.0, together with reduced apoptosis and elevated proliferation. Next, we investigated the mechanisms underlying atRA, Notch1 and MEE degradation in palate organ culture. Our results revealed that down-regulation of Notch1 partially rescued the inhibition of atRA-induced palate fusion. Molecular analysis indicated that atRA increased the expression of Notch1 and Rbpj and decreased the expression of P21. In addition, depletion of Notch1 expression decreased the expression of Rbpj and increased the expression of P21. Moreover, inhibition of Rbpj expression partially reversed atRA-induced MEE persistence and increased P21 expression. These findings demonstrate that atRA inhibits MEE degradation, which in turn induces a cleft palate, possibly through the Notch1/RBPjk/P21 signaling pathway. - Highlights: • atRA exposure on E12.0 induced MEE persistence and cleft palate. • Notch1 was up-regulated in MEE cells in the atRA-treated embryos. • atRA inhibits MEE degradation, which in turn induces cleft palate, possibly through the Notch1/RBPjk/P21 signaling pathway.

  17. Absence of Notch1 in murine myeloid cells attenuates the development of experimental autoimmune encephalomyelitis by affecting Th1 and Th17 priming.

    Science.gov (United States)

    Fernández, Miriam; Monsalve, Eva M; López-López, Susana; Ruiz-García, Almudena; Mellado, Susana; Caminos, Elena; García-Ramírez, José Javier; Laborda, Jorge; Tranque, Pedro; Díaz-Guerra, María José M

    2017-12-01

    Inhibition of Notch signalling in T cells attenuates the development of experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis. Growing evidence indicates that myeloid cells are also key players in autoimmune processes. Thus, the present study evaluates the role of the Notch1 receptor in myeloid cells on the progression of myelin oligodendrocyte glycoprotein (MOG) 35-55 -induced EAE, using mice with a myeloid-specific deletion of the Notch1 gene (MyeNotch1KO). We found that EAE progression was less severe in the absence of Notch1 in myeloid cells. Thus, histopathological analysis revealed reduced pathology in the spinal cord of MyeNotch1KO mice, with decreased microglia/astrocyte activation, demyelination and infiltration of CD4 + T cells. Moreover, these mice showed lower Th1 and Th17 cell infiltration and expression of IFN-γ and IL-17 mRNA in the spinal cord. Accordingly, splenocytes from MyeNotch1KO mice reactivated in vitro presented reduced Th1 and Th17 activation, and lower expression of IL-12, IL-23, TNF-α, IL-6, and CD86. Moreover, reactivated wild-type splenocytes showed increased Notch1 expression, arguing for a specific involvement of this receptor in autoimmune T cell activation in secondary lymphoid tissues. In summary, our results reveal a key role of the Notch1 receptor in myeloid cells for the initiation and progression of EAE. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  18. NOTCH1, NOTCH3, NOTCH4, and JAG2 protein levels in human endometrial cancer.

    Science.gov (United States)

    Sasnauskienė, Aušra; Jonušienė, Violeta; Krikštaponienė, Aurelija; Butkytė, Stasė; Dabkevičienė, Daiva; Kanopienė, Daiva; Kazbarienė, Birutė; Didžiapetrienė, Janina

    2014-01-01

    Notch signaling is a conserved developmental pathway, which plays an important role in the regulation of cell proliferation, differentiation and death. Deregulation of Notch pathway has been connected with the carcinogenesis in a variety of cancers. The aim of this study was to investigate the level of the Notch signaling pathway proteins (NOTCH1, 3, 4 and JAG2) in the samples from human endometrial cancer. The amount of the Notch receptors NOTCH1, 3, 4 and ligand JAG2 protein was determined by Western blot analysis in the samples from stage I endometrial cancer and adjacent nontumor endometrial tissue of 22 patients. The level of NOTCH4 receptor was 1.7 times lower in stage I endometrial cancer as compared with the healthy tissue of the same patients (P=0.04). The protein level of ligand JAG2 was significantly reduced by 2.5 times in stage IB endometrial adenocarcinoma samples (P=0.01). It was reduced in the majority of stage IB adenocarcinomas. There were no significant changes in the protein amount of NOTCH1 and NOTCH3 receptors comparing stage I endometrial adenocarcinoma and healthy tissues. The reduced amount of NOTCH4 and JAG2 proteins and the decreased level of mRNA coding Notch proteins, as reported in our previous studies, supports the notion that Notch pathway has rather tumor-suppressive than oncogenic role in human endometrial cancer cells. It suggests that Notch pathway activation is a potential therapeutic target. Copyright © 2014 Lithuanian University of Health Sciences. Production and hosting by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

  19. Restoration of p53 Expression in Human Cancer Cell Lines Upregulates the Expression of Notch1: Implications for Cancer Cell Fate Determination after Genotoxic Stress

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    Fatouma Alimirah

    2007-05-01

    Full Text Available Following genotoxic stress, transcriptional activation of target genes by p53 tumor suppressor is critical in cell fate determination. Here we report that the restoration of p53 function in human cancer cell lines that are deficient in p53 function upregulated the expression of Notch1. Interestingly, the expression of wild-type p53 in human prostate and breast cancer cell lines correlated well with increased expression of Notch1. Furthermore, knockdown of p53 expression in cancer cells that express wild-type p53 resulted in reduced expression of Notch1. Importantly, genotoxic stress to cancer cells that resulted in activation of p53 also upregulated the expression of Notch1. Moreover, p53mediated induction of Notch1 expression was associated with stimulation of the activity of Notch-responsive reporters. Notably, p53 differentially regulated the expression of Notch family members: expression of Notch2 and Notch4 was not induced by p53. Significantly, treatment of cells with gamma secretase inhibitor, an inhibitor of Notch signaling, increased susceptibility to apoptosis in response to genotoxic stress. Together, our observations suggest that p53mediated upregulation of Notch1 expression in human cancer cell lines contributes to cell fate determination after genotoxic stress.

  20. [Effects of arsenic trioxide on the proliferation of human breast cancer SKBR-3 cell and the expression of Notch1].

    Science.gov (United States)

    Li, You-Jian; Xia, Jun; Zhao, Rui

    2012-06-01

    To study the effects of arsenic trioxide (As2O3) on the proliferation and the migration force of human breast cancer SKBR-3 cell and the expression of Notch1. SKBR-3 cells were cultured with different concentrations of As2O3 for 24 h and with the final concentration of 8 micromol/L for 24, 48, and 72 h. The effects of As2O3 on the cell proliferation of SKBR-3 were detected by MTT assay. The effects of the migration force of SKBR-3 cells were detected by Transwell. The expression of Notch1 mRNA was detected using reverse transcription polymerase chain reaction (RT-PCR). The expression of Notch1 protein was detected using Western blot. As2O3 could significantly inhibit the proliferation of SKBR-3 cells in a concentration- and time-dependent manner (P breast cancer cells possibly through Notch1 signaling pathway, thus providing theoretical and experimental bases for treating breast cancer by arsenic.

  1. Astragalus injection attenuates bleomycin-induced pulmonary fibrosis via down-regulating Jagged1/Notch1 in lungs.

    Science.gov (United States)

    Zhou, Yan; Liao, Shiping; Zhang, Zhongwei; Wang, Bo; Wan, Lihong

    2016-03-01

    Inhibition of Notch signalling is a potential therapeutic strategy for pulmonary fibrosis. This study was designed to investigate the antifibrosis effects and possible mechanism of astragalus injection (AI) on bleomycin (BLM)-induced pulmonary fibrosis in rats. Pulmonary fibrosis was induced by intratracheal instillation of bleomycin (5 mg/kg) in male SD rats. All rats received daily intraperitoneally administration of dexamethasone (DEX, 3 mg/kg), astragalus injection (AI, 8 g/kg) or saline 1 day after bleomycin instillation daily for 28 days. Histological changes in the lung were evaluated by haematoxylin and eosin and Masson's trichrome staining. The expression of α-smooth muscle protein (α-SMA) was assayed by immunohistochemical (IHC). The mRNA and protein level of Jagged1, Notch1 and transforming growth factor-β1 (TGF-β1) was analysed by qPCR and Western blot. BLM-induced severe alveolitis and pulmonary fibrosis; together with significant elevation of α-SMA, TGF-β1, Jagged1 and Notch1. Astragalus injection (AI, 8 g/kg) administration notably attenuated the degree of alveolitis and lung fibrosis, and markedly reduced the elevated levels of α-SMA, TGF-β1, Jagged1 and Notch1 in lungs. Astragalus injection (AI, 8 g/kg) may exert protective effects on bleomycin-induced pulmonary fibrosis via downregulating Jagged1/Notch1 in lung. © 2016 Royal Pharmaceutical Society, Journal of Pharmacy and Pharmacology.

  2. β-Elemene-Attenuated Tumor Angiogenesis by Targeting Notch-1 in Gastric Cancer Stem-Like Cells

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    Bing Yan

    2013-01-01

    Full Text Available Emerging evidence suggests that cancer stem cells are involved in tumor angiogenesis. The Notch signaling pathway is one of the most important regulators of these processes. β-Elemene, a naturally occurring compound extracted from Curcumae Radix, has been used as an antitumor drug for various cancers in China. However, its underlying mechanism in the treatment of gastric cancer remains largely unknown. Here, we report that CD44+ gastric cancer stem-like cells (GCSCs showed enhanced proliferation capacity compared to their CD44− counterparts, and this proliferation was accompanied by the high expression of Notch-1 (in vitro. These cells were also more superior in spheroid colony formation (in vitro and tumorigenicity (in vivo and positively associated with microvessel density (in vivo. β-Elemene was demonstrated to effectively inhibit the viability of GCSCs in a dose-dependent manner, most likely by suppressing Notch-1 (in vitro. β-Elemene also contributed to growth suppression and attenuated the angiogenesis capacity of these cells (in vivo most likely by interfering with the expression of Notch-1 but not with Dll4. Our findings indicated that GCSCs play an important role in tumor angiogenesis, and Notch-1 is one of the most likely mediators involved in these processes. β-Elemene was effective at attenuating angiogenesis by targeting the GCSCs, which could be regarded as a potential mechanism for its efficacy in gastric cancer management in the future.

  3. Estrogen receptor β-dependent Notch1 activation protects vascular endothelium against tumor necrosis factor α (TNFα)-induced apoptosis.

    Science.gov (United States)

    Fortini, Francesca; Vieceli Dalla Sega, Francesco; Caliceti, Cristiana; Aquila, Giorgio; Pannella, Micaela; Pannuti, Antonio; Miele, Lucio; Ferrari, Roberto; Rizzo, Paola

    2017-11-03

    Unlike age-matched men, premenopausal women benefit from cardiovascular protection. Estrogens protect against apoptosis of endothelial cells (ECs), one of the hallmarks of endothelial dysfunction leading to cardiovascular disorders, but the underlying molecular mechanisms remain poorly understood. The inflammatory cytokine TNFα causes EC apoptosis while dysregulating the Notch pathway, a major contributor to EC survival. We have previously reported that 17β-estradiol (E2) treatment activates Notch signaling in ECs. Here, we sought to assess whether in TNFα-induced inflammation Notch is involved in E2-mediated protection of the endothelium. We treated human umbilical vein endothelial cells (HUVECs) with E2, TNFα, or both and found that E2 counteracts TNFα-induced apoptosis. When Notch1 was inhibited, this E2-mediated protection was not observed, whereas ectopic overexpression of Notch1 diminished TNFα-induced apoptosis. Moreover, TNFα reduced the levels of active Notch1 protein, which were partially restored by E2 treatment. Moreover, siRNA-mediated knockdown of estrogen receptor β (ERβ), but not ERα, abolished the effect of E2 on apoptosis. Additionally, the E2-mediated regulation of the levels of active Notch1 was abrogated after silencing ERβ. In summary, our results indicate that E2 requires active Notch1 through a mechanism involving ERβ to protect the endothelium in TNFα-induced inflammation. These findings could be relevant for assessing the efficacy and applicability of menopausal hormone treatment, because they may indicate that in women with impaired Notch signaling, hormone therapy might not effectively protect the endothelium. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

  4. Notch1-WISP-1 axis determines the regulatory role of mesenchymal stem cell-derived stromal fibroblasts in melanoma metastasis.

    Science.gov (United States)

    Shao, Hongwei; Cai, Long; Moller, Mecker; Issac, Biju; Zhang, Leiming; Owyong, Mark; Moscowitz, Anna Elizabeth; Vazquez-Padron, Roberto; Radtke, Freddy; Liu, Zhao-Jun

    2016-11-29

    Mesenchymal stem cells-derived fibroblasts (MSC-DF) constitute a significant portion of stromal fibroblasts in the tumor microenvironment (TME) and are key modulators of tumor progression. However, the molecular mechanisms that determine their tumor-regulatory function are poorly understood. Here, we uncover the Notch1 pathway as a molecular determinant that selectively controls the regulatory role of MSC-DF in melanoma metastasis. We demonstrate that the Notch1 pathway's activity is inversely correlated with the metastasis-regulating function of fibroblasts and can determine the metastasis-promoting or -suppressing phenotype of MSC-DF. When co-grafted with melanoma cells, MSC-DFNotch1-/- selectively promote, while MSC-DFN1IC+/+ preferentially suppress melanoma metastasis, but not growth, in mouse models. Consistently, conditioned media (CM) from MSC-DFNotch1-/- and MSC-DFN1IC+/+ oppositely, yet selectively regulates migration, but not growth of melanoma cells in vitro. Additionally, when co-cultured with metastatic melanoma cells in vitro, MSC-DFNotch1-/- support, while MSC-DFN1IC+/+ inhibit melanoma cells in the formation of spheroids. These findings expand the repertoire of Notch1 signaling as a molecular switch in determining the tumor metastasis-regulating function of MSC-DF. We also identified Wnt-induced secreted protein-1 (WISP-1) as a key downstream secretory mediator of Notch1 signaling to execute the influential role of MSC-DF on melanoma metastasis. These findings reveal the Notch1-WISP-1 axis as a crucial molecular determinant in governing stromal regulation of melanoma metastasis; thus, establishing this axis as a potential therapeutic target for melanoma metastasis.

  5. The jagged-2/notch-1/hes-1 pathway is involved in intestinal epithelium regeneration after intestinal ischemia-reperfusion injury.

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    Guoqing Chen

    Full Text Available Notch signaling plays a critical role in the maintenance of intestinal crypt epithelial cell proliferation. The aim of this study was to investigate the role of Notch signaling in the proliferation and regeneration of intestinal epithelium after intestinal ischemia reperfusion (I/R injury.Male Sprague-Dawley rats were subjected to sham operation or I/R by occlusion of the superior mesenteric artery (SMA for 20 min. Intestinal tissue samples were collected at 0, 1, 2, 4, and 6 h after reperfusion. Proliferation of the intestinal epithelium was evaluated by immunohistochemical staining of proliferating nuclear antigen (PCNA. The mRNA and protein expression levels of Notch signaling components were examined using Real-time PCR and Western blot analyses. Immunofluorescence was also performed to detect the expression and location of Jagged-2, cleaved Notch-1, and Hes-1 in the intestine. Finally, the γ-secretase inhibitor DAPT and the siRNA for Jagged-2 and Hes-1 were applied to investigate the functional role of Notch signaling in the proliferation of intestinal epithelial cells in an in vitro IEC-6 culture system.I/R injury caused increased intestinal crypt epithelial cell proliferation and increased mRNA and protein expression of Jagged-2, Notch-1, and Hes-1. The immunofluorescence results further confirmed increased protein expression of Jagged-2, cleaved Notch-1, and Hes-1 in the intestinal crypts. The inhibition of Notch signaling with DAPT and the suppression of Jagged-2 and Hes-1 expression using siRNA both significantly inhibited the proliferation of IEC-6 cells.The Jagged-2/Notch-1/Hes-1 signaling pathway is involved in intestinal epithelium regeneration early after I/R injury by increasing crypt epithelial cell proliferation.

  6. Compound heterozygous NOTCH1 mutations underlie impaired cardiogenesis in a patient with hypoplastic left heart syndrome.

    Science.gov (United States)

    Theis, Jeanne L; Hrstka, Sybil C L; Evans, Jared M; O'Byrne, Megan M; de Andrade, Mariza; O'Leary, Patrick W; Nelson, Timothy J; Olson, Timothy M

    2015-09-01

    Hypoplastic left heart syndrome (HLHS) is a severe congenital heart defect (CHD) that necessitates staged, single ventricle surgical palliation. An increased frequency of bicuspid aortic valve (BAV) has been observed among relatives. We postulated number of mutant alleles as a molecular basis for variable CHD expression in an extended family comprised of an HLHS proband and four family members who underwent echocardiography and whole-genome sequencing (WGS). Dermal fibroblast-derived induced pluripotent stem cells (iPSC) were procured from the proband-parent trio and bioengineered into cardiomyocytes. Cardiac phenotyping revealed aortic valve atresia and a slit-like left ventricular cavity in the HLHS proband, isolated bicuspid pulmonary valve in his mother, BAV in a maternal 4° relative, and no CHD in his father or sister. Filtering of WGS for rare, functional variants that segregated with CHD and were compound heterozygous in the HLHS proband identified NOTCH1 as the sole candidate gene. An unreported missense mutation (P1964L) in the cytoplasmic domain, segregating with semilunar valve malformation, was maternally inherited and a rare missense mutation (P1256L) in the extracellular domain, clinically silent in the heterozygous state, was paternally inherited. Patient-specific iPSCs exhibited diminished transcript levels of NOTCH1 signaling pathway components, impaired myocardiogenesis, and a higher prevalence of heterogeneous myofilament organization. Extended, phenotypically characterized families enable WGS-derived variant filtering for plausible Mendelian modes of inheritance, a powerful strategy to discover molecular underpinnings of CHD. Identification of compound heterozygous NOTCH1 mutations and iPSC-based functional modeling implicate mutant allele burden and impaired myogenic potential as mechanisms for HLHS.

  7. Buyang Huanwu decoction up-regulates Notch1 gene expression in injured spinal cord

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    Zhan-peng Guo

    2015-01-01

    Full Text Available Expression of genes in the Notch signaling pathway is altered in the injured spinal cord, which indicates that Notch participates in repair after spinal cord injury. Buyang Huanwu decoction, a traditional Chinese herbal preparation, can promote the growth of nerve cells and nerve fibers; however, it is unclear whether Buyang Huanwu decoction affects the Notch signaling pathway in injured spinal cord. In this study, a rat model was established by injuring the T 10 spinal cord. At 2 days after injury, rats were intragastrically administered 2 mL of 0.8 g/mL Buyang Huanwu decoction daily until sacrifice. Real-time reverse transcription polymerase chain reaction analysis demonstrated that at 7, 14 and 28 days after injury, the expression of Notch1 was increased in the Buyang Huanwu decoction group compared with controls. These findings confirm that Buyang Huanwu decoction can promote the expression of Notch1 in rats with incomplete spinal cord injury, and may indicate a mechanism to promote the repair of spinal cord injury.

  8. [Inhibitory effects of Notch1 overexpression on proliferation and neuroendocrine marker expression in a small cell lung cancer cell line].

    Science.gov (United States)

    Wang, Jie-Xin; Zhang, Xiu-ming; Wang, Ling-ling; Cheng, Hui; Yao, Gen-you

    2009-05-01

    To investigate the effects of Notch1 signal activation on proliferation and neuroendocrine marker expression in small cell lung cancer cells. The active form of Notch1 (NIC) was over-expressed in NCI-H446 cells by constitutive transfection and a stable transfected cell line was established. Proliferation of NCI-H446 cells was analysed by MTT assay on 6 successive days. Expression of neuroendocrine markers (CgA, NSE) was observed by immunohistochemistry and Western blot analysis. Statistical analysis was conducted to compare the results in cells with NIC transfected and those in control groups. MTT assay showed that absorbance (A) of cells overexpressing Notch1 was significantly depressed compared with that of the control cells (PNIC transfected group, sham group and negative control group were 8.81 +/- 0.77, 38.10 +/- 1.55, 38.97 +/- 0.80, respectively, the former one was significantly smaller than that of the latter two (PNIC transfected group, sham group and negative control group were 7.21 +/- 0.59, 28.25 +/- 1.46, 30.57 +/- 1.31, respectively, the former one was significantly smaller than that in the latter two (PNIC transfected group and sham group were 0.54 +/- 0.03 and 0.99 +/- 0.05, respectively, (gray scale of the negative control set as 1.00), the former one was significantly smaller than that of the other two groups (PNIC transfected group and sham group were 0.43 +/- 0.02 and 1.07 +/- 0.09, respectively (gray scale of the negative control set as 1.00), the former one was significantly smaller than that of the other two groups (P<0.01). Notch1 may behave as a tumor suppressor in small cell lung cancer. Notch1 signal activation can inhibit the proliferation and neuroendocrine marker expression in small cell lung cancer cells, suggesting that Notch1 gene could be a new target for small cell lung cancer treatment and probable relief of paraneoplastic syndrome.

  9. Multifactorial ERβ and NOTCH1 control of squamous differentiation and cancer

    Science.gov (United States)

    Brooks, Yang Sui; Ostano, Paola; Jo, Seung-Hee; Dai, Jun; Getsios, Spiro; Dziunycz, Piotr; Hofbauer, Günther F.L.; Cerveny, Kara; Chiorino, Giovanna; Lefort, Karine; Dotto, G. Paolo

    2014-01-01

    Downmodulation or loss-of-function mutations of the gene encoding NOTCH1 are associated with dysfunctional squamous cell differentiation and development of squamous cell carcinoma (SCC) in skin and internal organs. While NOTCH1 receptor activation has been well characterized, little is known about how NOTCH1 gene transcription is regulated. Using bioinformatics and functional screening approaches, we identified several regulators of the NOTCH1 gene in keratinocytes, with the transcription factors DLX5 and EGR3 and estrogen receptor β (ERβ) directly controlling its expression in differentiation. DLX5 and ERG3 are required for RNA polymerase II (PolII) recruitment to the NOTCH1 locus, while ERβ controls NOTCH1 transcription through RNA PolII pause release. Expression of several identified NOTCH1 regulators, including ERβ, is frequently compromised in skin, head and neck, and lung SCCs and SCC-derived cell lines. Furthermore, a keratinocyte ERβ–dependent program of gene expression is subverted in SCCs from various body sites, and there are consistent differences in mutation and gene-expression signatures of head and neck and lung SCCs in female versus male patients. Experimentally increased ERβ expression or treatment with ERβ agonists inhibited proliferation of SCC cells and promoted NOTCH1 expression and squamous differentiation both in vitro and in mouse xenotransplants. Our data identify a link between transcriptional control of NOTCH1 expression and the estrogen response in keratinocytes, with implications for differentiation therapy of squamous cancer. PMID:24743148

  10. Notch-1 and notch-4 receptors as prognostic markers in breast cancer.

    Science.gov (United States)

    Yao, Katharine; Rizzo, Paola; Rajan, Prabha; Albain, Kathy; Rychlik, Karen; Shah, Sneha; Miele, Lucio

    2011-10-01

    Studies looking at immunohistochemical (IHC) staining of Notch receptors in breast cancer and correlation with known prognostic factors are sparse. IHC staining for nuclear, cytoplasmic, and membrane Notch-1 (N1), Notch-4 (N4), and Jagged-1 (JAG1) was performed and correlated with known prognostic factors. Of 48 breast cancers, 36 (67%) were invasive, mean age was 50 years (range 43-86 years), 37 (77%) were estrogen receptor (ERα) positive, and 13 (27%) node positive. There was significantly more marked N1 membranous staining in ERα-positive tumors (P membranous N4 significantly correlated with Ki67 (P membranous JAG1 significantly correlated with Ki67 (P markers is feasible and correlates with known prognostic factors consistent with a biological role of Notch signaling in breast cancer progression.

  11. Down-regulation of Notch-1 by γ-secretase inhibitor suppress the ...

    African Journals Online (AJOL)

    We investigated whether DAPT plays a role in the regulation of the proliferation and migration of prostate cancer cells through down-regulation of the Notch-1 activation. Here, we reported that DAPT treatment inhibited the PC cells proliferation and migration in dose- and time- dependent manner. The expression of Notch-1 ...

  12. Notch1 maintains dormancy of olfactory horizontal basal cells, a reserve neural stem cell.

    Science.gov (United States)

    Herrick, Daniel B; Lin, Brian; Peterson, Jesse; Schnittke, Nikolai; Schwob, James E

    2017-07-11

    The remarkable capacity of the adult olfactory epithelium (OE) to regenerate fully both neurosensory and nonneuronal cell types after severe epithelial injury depends on life-long persistence of two stem cell populations: the horizontal basal cells (HBCs), which are quiescent and held in reserve, and mitotically active globose basal cells. It has recently been demonstrated that down-regulation of the ΔN form of the transcription factor p63 is both necessary and sufficient to release HBCs from dormancy. However, the mechanisms by which p63 is down-regulated after acute OE injury remain unknown. To identify the cellular source of potential signaling mechanisms, we assessed HBC activation after neuron-only and sustentacular cell death. We found that ablation of sustentacular cells is sufficient for HBC activation to multipotency. By expression analysis, next-generation sequencing, and immunohistochemical examination, down-regulation of Notch pathway signaling is coincident with HBC activation. Therefore, using HBC-specific conditional knockout of Notch receptors and overexpression of N1ICD, we show that Notch signaling maintains p63 levels and HBC dormancy, in contrast to its suppression of p63 expression in other tissues. Additionally, Notch1, but not Notch2, is required to maintain HBC dormancy after selective neuronal degeneration. Taken together, our data indicate that the activation of HBCs observed after tissue injury or sustentacular cell ablation is caused by the reduction/elimination of Notch signaling on HBCs; elimination of Jagged1 expressed by sustentacular cells may be the ligand responsible.

  13. Perivascular delivery of Notch 1 siRNA inhibits injury-induced arterial remodeling.

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    Eileen M Redmond

    Full Text Available To determine the efficacy of perivascular delivery of Notch 1 siRNA in preventing injury-induced arterial remodeling.Carotid artery ligation was performed to induce arterial remodeling. After 14 days, morphometric analysis confirmed increased vSMC growth and subsequent media thickening and neointimal formation. Laser capture microdissection, quantitative qRT-PCR and immunoblot analysis of medial tissue revealed a significant increase in Notch1 receptor and notch target gene, Hrt 1 and 2 expression in the injured vessels. Perivascular delivery of Notch 1 siRNA by pluronic gel inhibited the injury-induced increase in Notch 1 receptor and target gene expression when compared to scrambled siRNA controls while concomitantly reducing media thickening and neointimal formation to pre-injury, sham-operated levels. Selective Notch 1 knockdown also reversed the injury-induced inhibition of pro-apoptotic Bax expression while decreasing injury-induced anti-apoptotic Bcl-XL expression to sham-operated control levels. In parallel experiments, proliferative cyclin levels, as measured by PCNA expression, were reversed to sham-operated control levels following selective Notch 1 knockdown.These results suggest that injury-induced arterial remodeling can be successfully inhibited by localized perivascular delivery of Notch 1 siRNA.

  14. Evidence of Aortopathy in Mice with Haploinsufficiency of Notch1 in Nos3-Null Background

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    Sara N. Koenig

    2015-03-01

    Full Text Available Thoracic aortic aneurysms (TAA are a significant cause of morbidity and mortality in humans. While the exact etiology is unknown, genetic factors play an important role. Mutations in NOTCH1 have been linked to bicuspid aortic valve (BAV and aortopathy in humans. The aim of this study was to determine if haploinsufficiency of Notch1 contributes to aortopathy using Notch1+/−; Nos3−/− mice. Echocardiographic analysis of Notch1+/−; Nos3−/− mice reveals effacement of the sinotubular junction and a trend toward dilation of the aortic sinus. Furthermore, examination of the proximal aorta of Notch1+/−; Nos3−/− mice reveals elastic fiber degradation, a trend toward increased matrix metalloproteinase 2 expression, and increased smooth muscle cell apoptosis, features characteristic of aneurysmal disease. Although at a lower penetrance, we also found features consistent with aortopathic changes in Notch1 heterozygote mice and in Nos3-null mice. Our findings implicate a novel role for Notch1 in aortopathy of the proximal aorta.

  15. Human disease modeling reveals integrated transcriptional and epigenetic mechanisms of NOTCH1 haploinsufficiency.

    Science.gov (United States)

    Theodoris, Christina V; Li, Molong; White, Mark P; Liu, Lei; He, Daniel; Pollard, Katherine S; Bruneau, Benoit G; Srivastava, Deepak

    2015-03-12

    The mechanisms by which transcription factor haploinsufficiency alters the epigenetic and transcriptional landscape in human cells to cause disease are unknown. Here, we utilized human induced pluripotent stem cell (iPSC)-derived endothelial cells (ECs) to show that heterozygous nonsense mutations in NOTCH1 that cause aortic valve calcification disrupt the epigenetic architecture, resulting in derepression of latent pro-osteogenic and -inflammatory gene networks. Hemodynamic shear stress, which protects valves from calcification in vivo, activated anti-osteogenic and anti-inflammatory networks in NOTCH1(+/+), but not NOTCH1(+/-), iPSC-derived ECs. NOTCH1 haploinsufficiency altered H3K27ac at NOTCH1-bound enhancers, dysregulating downstream transcription of more than 1,000 genes involved in osteogenesis, inflammation, and oxidative stress. Computational predictions of the disrupted NOTCH1-dependent gene network revealed regulatory nodes that, when modulated, restored the network toward the NOTCH1(+/+) state. Our results highlight how alterations in transcription factor dosage affect gene networks leading to human disease and reveal nodes for potential therapeutic intervention. Copyright © 2015 Elsevier Inc. All rights reserved.

  16. Signal processing in a randomly time varying system.

    Science.gov (United States)

    Adomian, G.

    1972-01-01

    Stochastic operators are applied to an analysis of some deterministic systems of signal transformation. The distribution of a random process at the output of a system is given through its distribution at the input and through a stochastic Green's function. A two-point correlation function is derived to obtain a solution to differential equations which contain coefficients, boundary conditions, or right-hand terms representing random processes.

  17. Notch1—WISP-1 axis determines the regulatory role of mesenchymal stem cell-derived stromal fibroblasts in melanoma metastasis

    Science.gov (United States)

    Moller, Mecker; Issac, Biju; Zhang, Leiming; Owyong, Mark; Moscowitz, Anna Elizabeth; Vazquez-Padron, Roberto; Radtke, Freddy; Liu, Zhao-Jun

    2016-01-01

    Mesenchymal stem cells-derived fibroblasts (MSC-DF) constitute a significant portion of stromal fibroblasts in the tumor microenvironment (TME) and are key modulators of tumor progression. However, the molecular mechanisms that determine their tumor-regulatory function are poorly understood. Here, we uncover the Notch1 pathway as a molecular determinant that selectively controls the regulatory role of MSC-DF in melanoma metastasis. We demonstrate that the Notch1 pathway's activity is inversely correlated with the metastasis-regulating function of fibroblasts and can determine the metastasis-promoting or -suppressing phenotype of MSC-DF. When co-grafted with melanoma cells, MSC-DFNotch1−/− selectively promote, while MSC-DFN1IC+/+ preferentially suppress melanoma metastasis, but not growth, in mouse models. Consistently, conditioned media (CM) from MSC-DFNotch1−/− and MSC-DFN1IC+/+ oppositely, yet selectively regulates migration, but not growth of melanoma cells in vitro. Additionally, when co-cultured with metastatic melanoma cells in vitro, MSC-DFNotch1−/− support, while MSC-DFN1IC+/+ inhibit melanoma cells in the formation of spheroids. These findings expand the repertoire of Notch1 signaling as a molecular switch in determining the tumor metastasis-regulating function of MSC-DF. We also identified Wnt-induced secreted protein-1 (WISP-1) as a key downstream secretory mediator of Notch1 signaling to execute the influential role of MSC-DF on melanoma metastasis. These findings reveal the Notch1—WISP-1 axis as a crucial molecular determinant in governing stromal regulation of melanoma metastasis; thus, establishing this axis as a potential therapeutic target for melanoma metastasis. PMID:27813493

  18. Prognostic value of Notch-1 expression in hepatocellular carcinoma: a meta-analysis

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    Wu T

    2015-10-01

    Full Text Available Tao Wu,1 Min Jiao,1 Li Jing,1 Min-Cong Wang,1 Hai-Feng Sun,2 Qing Li,1 Yi-Yang Bai,1 Yong-Chang Wei,1 Ke-Jun Nan,1 Hui Guo1 1Department of Medical Oncology, The First Affiliated Hospital of Xi’an Jiaotong University, 2Department of Oncology, Shaanxi Cancer Hospital, Xi’an, People’s Republic of China Abstract: Association of Notch-1 expression with prognosis of patients with hepatocellular carcinoma (HCC remains controversial. We conducted a meta-analysis to reevaluate the association of Notch-1 expression with clinicopathological characteristics and prognosis of HCC. PubMed, Embase, Web of Science, and China National Knowledge Infrastructure were searched to look for relevant studies. The association between Notch-1 expression and clinicopathological parameters and overall survival (OS was then reassessed using the meta-analysis for odds ratio (OR or hazard ratio (HR and 95% confidence interval (CI. A total of seven studies, including 810 HCC patients, were eligible for the meta-analysis. Our data showed that high Notch-1 expression was able to predict poor OS (HR 1.50, 95% CI 1.17–1.83, P=0.0001. The pooled OR showed that high Notch-1 expression was significantly associated with tumor metastasis (OR 0.37, 95% CI 0.16–0.86, P=0.02 and tumor size >5 cm (OR 0.48, 95% CI 0.26–0.88, P=0.02. In contrast, there was no association between high Notch-1 expression and tumor differentiation, late TNM stage, tumor number, and portal vein invasion of HCC. In conclusion, Notch-1 overexpression might predict poorer survival and more aggressive behavior in patients with HCC. Keywords: hepatocellular carcinoma, Notch-1, prognosis, clinicopathological features, meta-analysis

  19. miR-935 suppresses gastric signet ring cell carcinoma tumorigenesis by targeting Notch1 expression

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    Yan, Chao [Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100730 (China); Yu, Jianchun, E-mail: yu_jchpumch@163.com [Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100730 (China); Kang, Weiming [Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100730 (China); Liu, Yuqin [Cell Culture Center, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100005 (China); Ma, Zhiqiang; Zhou, Li [Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100730 (China)

    2016-01-29

    Gastric signet ring cell carcinoma (GSRCC) is a unique pathological type of gastric carcinoma that is extremely invasive and has a poor prognosis. Expression of microRNAs (miRNAs) has been closely linked to the carcinogenesis of gastric cancer and has been considered as a powerful prognostic marker. The function of miR-935 has never been reported in cancer before. We found, using microRNA array, that expression of miR-935 in GSRCC cell lines is lower than in non-GSRCC cell lines, and enhanced expression of miR-935 in GSRCC cell-lines inhibit cell proliferation, migration and invasion. We also identified Notch1 as a direct target of miR-935. Knockdown of Notch1 reduced proliferation, migration/invasion of GSRCC cells, and overexpression Notch1's activated form (Notch intracellular domain) could rescue miR-935's tumor suppressive effect on GSRCC. Expression of miR-935 was lower in gastric carcinoma tissue than in paired normal tissue samples, and lower in GSRCC than in non-GSRCC. Our results demonstrate the inverse correlation between the expression of miR-935 and Notch1 in gastric tissues. We conclude that miR-935 inhibits gastric carcinoma cell proliferation, migration and invasion by targeting Notch1, suggesting potential applications of the miR-935-Notch1 pathway in gastric cancer clinical diagnosis and therapeutics, especially in gastric signet ring cell carcinoma. - Highlights: • The expression of miR-935 is lower in GC tissue than in paired normal tissue. • The expression of miR-935 is lower in GSRCC tissue than in non-GSRCC. • Enhanced expression of miR-935 suppresses tumorigenesis of GSRCC. • Notch1 is a direct target of miR-935.

  20. Expression of Notch 1 receptor associated with tumor aggressiveness in papillary thyroid carcinoma

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    Fu H

    2016-03-01

    Full Text Available Hongliang Fu,1 Chao Ma,1 Wenbin Guan,2 Weiwei Cheng,1 Fang Feng,1 Hui Wang1 1Department of Nuclear Medicine, 2Department of Pathology, Xin Hua Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai, People’s Republic of China Aim: The aim of this study was to assess if the expression of Notch 1 receptor is associated with tumor aggressiveness in papillary thyroid carcinomas (PTCs.Patients and methods: By searching the electronic medical record system of Xin Hua Hospital, all cases of PTC patients who underwent thyroidectomy in the hospital between 2013 and 2014 were retrieved. Then, the cases of patients who had a history of any other malignancy or whose thyroid tumor specimen was not available for assay were rejected. Finally, 68 cases of PTC patients were obtained. Formalin-fixed paraffin-embedded tissue blocks of these patients were studied by immunohistochemistry to learn the expression of Notch 1 receptor. Meanwhile, the clinical data of these patients including sex, age, size of the tumor, presence of node metastasis or distant metastasis, and presence of capsule invasion and tumor multicentricity were collected. Pearson’s chi-square test or Fisher’s exact test was used for measuring statistical differences in categorical variables. All the statistical tests were two-sided. A P-value <0.05 was considered to be statistically significant.Results: A total of 19 male and 49 female PTC patients with a mean age of 44.8±13.6 years (range 18–78 years were studied. Notch 1 receptor expression was found in 15/68 (22% samples of PTC. The expression of Notch 1 receptor was significantly associated with tumor size (P=0.021, distant metastasis (P=0.008, capsule invasion (P=0.001, tumor multicentricity (P=0.018, and age (P=0.033. However, the expression of Notch 1 receptor was not significantly correlated with node metastasis (P=0.096 and sex (P=0.901.Conclusion: The expression of Notch 1 receptor is associated with tumor

  1. Epidermal growth factor receptor inhibition reduces angiogenesis via hypoxia-inducible factor-1α and Notch1 in head neck squamous cell carcinoma.

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    Wei-Ming Wang

    Full Text Available Angiogenesis, a marker of cancer development, affects response to radiotherapy sensibility. This preclinical study aims to understand the receptor tyrosine kinase-mediated angiogenesis in head neck squamous cell carcinoma (HNSCC. The receptor tyrosine kinase activity in a transgenic mouse model of HNSCC was assessed. The anti-tumorigenetic and anti-angiogenetic effects of cetuximab-induced epidermal growth factor receptor (EGFR inhibition were investigated in xenograft and transgenic mouse models of HNSCC. The signaling transduction of Notch1 and hypoxia-inducible factor-1α (HIF-1α was also analyzed. EGFR was overexpressed and activated in the Tgfbr1/Pten deletion (2cKO mouse model of HNSCC. Cetuximab significantly delayed tumor onset by reducing tumor angiogenesis. This drug exerted similar effects on heterotopic xenograft tumors. In the human HNSCC tissue array, increased EGFR expression correlated with increased HIF-1α and micro vessel density. Cetuximab inhibited tumor-induced angiogenesis in vitro and in vivo by significantly downregulating HIF-1α and Notch1. EGFR is involved in the tumor angiogenesis of HNSCC via the HIF-1α and Notch1 pathways. Therefore, targeting EGFR by suppressing hypoxia- and Notch-induced angiogenesis may benefit HNSCC therapy.

  2. TNF inhibits Notch-1 in skeletal muscle cells by Ezh2 and DNA methylation mediated repression: implications in duchenne muscular dystrophy.

    Directory of Open Access Journals (Sweden)

    Swarnali Acharyya

    2010-08-01

    Full Text Available Classical NF-kappaB signaling functions as a negative regulator of skeletal myogenesis through potentially multiple mechanisms. The inhibitory actions of TNFalpha on skeletal muscle differentiation are mediated in part through sustained NF-kappaB activity. In dystrophic muscles, NF-kappaB activity is compartmentalized to myofibers to inhibit regeneration by limiting the number of myogenic progenitor cells. This regulation coincides with elevated levels of muscle derived TNFalpha that is also under IKKbeta and NF-kappaB control.Based on these findings we speculated that in DMD, TNFalpha secreted from myotubes inhibits regeneration by directly acting on satellite cells. Analysis of several satellite cell regulators revealed that TNFalpha is capable of inhibiting Notch-1 in satellite cells and C2C12 myoblasts, which was also found to be dependent on NF-kappaB. Notch-1 inhibition occurred at the mRNA level suggesting a transcriptional repression mechanism. Unlike its classical mode of action, TNFalpha stimulated the recruitment of Ezh2 and Dnmt-3b to coordinate histone and DNA methylation, respectively. Dnmt-3b recruitment was dependent on Ezh2.We propose that in dystrophic muscles, elevated levels of TNFalpha and NF-kappaB inhibit the regenerative potential of satellite cells via epigenetic silencing of the Notch-1 gene.

  3. Developmental exposure to 2,3,7,8 tetrachlorodibenzo-p-dioxin attenuates later-life Notch1-mediated T cell development and leukemogenesis

    Energy Technology Data Exchange (ETDEWEB)

    Ahrenhoerster, Lori S.; Leuthner, Tess C.; Tate, Everett R.; Lakatos, Peter A.; Laiosa, Michael D., E-mail: laiosa@uwm.edu

    2015-03-01

    Over half of T cell acute lymphoblastic leukemia (T-ALL) patients have activating mutations in the Notch gene. Moreover, the contaminant 2,3,7,8 tetrachlorodibenzo-p-dioxin (TCDD) is a known carcinogen that mediates its toxicity through the aryl hydrocarbon receptor (AHR), and crosstalk between activated AHR and Notch signaling pathways has previously been observed. Given the importance of Notch signaling in thymocyte development and T-ALL disease progression, we hypothesized that the activated AHR potentiates disease initiation and progression in an in vivo model of Notch1-induced thymoma. This hypothesis was tested utilizing adult and developmental exposure paradigms to TCDD in mice expressing a constitutively active Notch1 transgene (Notch{sup ICN-TG}). Following exposure of adult Notch{sup ICN-TG} mice to a single high dose of TCDD, we observed a significant increase in the efficiency of CD8 thymocyte generation. We next exposed pregnant mice to 3 μg/kg of TCDD throughout gestation and lactation to elucidate effects of developmental AHR activation on later-life T cell development and T-ALL-like thymoma susceptibility induced by Notch1. We found that the vehicle-exposed Notch{sup ICN-TG} offspring have a peripheral T cell pool heavily biased toward the CD4 lineage, while TCDD-exposed Notch{sup ICN-TG} offspring were biased toward the CD8 lineage. Furthermore, while the vehicle-exposed NotchICN-TG mice showed increased splenomegaly and B to T cell ratios indicative of disease, mice developmentally exposed to TCDD were largely protected from disease. These studies support a model where developmental AHR activation attenuates later-life Notch1-dependent impacts on thymocyte development and disease progression. - Highlights: • Adult mice exposed to 30 μg/kg TCDD have higher efficiency of CD8 thymocyte generation. • Mice carrying a constitutively active Notch transgene were exposed to 3 μg/kg TCDD throughout development. • Progression of Notch

  4. Alleviating Border Effects in Wavelet Transforms for Nonlinear Time-varying Signal Analysis

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    SU, H.

    2011-08-01

    Full Text Available Border effects are very common in many finite signals analysis and processing approaches using convolution operation. Alleviating the border effects that can occur in the processing of finite-length signals using wavelet transform is considered in this paper. Traditional methods for alleviating the border effects are suitable to compression or coding applications. We propose an algorithm based on Fourier series which is proved to be appropriate to the application of time-frequency analysis of nonlinear signals. Fourier series extension method preserves the time-varying characteristics of the signals. A modified signal duration expression for measuring the extent of border effects region is presented. The proposed algorithm is confirmed to be efficient to alleviate the border effects in comparison to the current methods through the numerical examples.

  5. A coherent digital demodulator for multiple signal formats and widely varying data rates

    Science.gov (United States)

    Mcguffin, Bruce F.

    1989-01-01

    The Tracking and Data Relay Satellite System (TDRSS) uses four ground station demodulators for K-band signals with data rates from 1 kb/s to 300 Mb/s. The author discusses the feasibility of replacing these demodulators with a single digital demodulator that may be reconfigured by altering stored parameters to accommodate all signal formats and data rates. This implementation will reduce total ground station cost and facilitate automation of ground station operation. Analysis of system performance concentrates on the carrier tracking loop. Analytic and simulation results relate system performance to parameter values and signal format as data rate and power vary independently on the In-phase and quadrature channels. It is demonstrated that a single digital demodulator can support TDRSS-compatible signals at data rates conservatively extending from 1K symbols/s to 10M symbols/s, using off-the-shelf hardware with 6 or more bits of accuracy.

  6. Acupuncture inhibits Notch1 and Hes1 protein expression in the basal ganglia of rats with cerebral hemorrhage

    Directory of Open Access Journals (Sweden)

    Wei Zou

    2015-01-01

    Full Text Available Notch pathway activation maintains neural stem cells in a proliferating state and increases nerve repair capacity. To date, studies have rarely focused on changes or damage to signal transduction pathways during cerebral hemorrhage. Here, we examined the effect of acupuncture in a rat model of cerebral hemorrhage. We examined four groups: in the control group, rats received no treatment. In the model group, cerebral hemorrhage models were established by infusing non-heparinized blood into the brain. In the acupuncture group, modeled rats had Baihui (DU20 and Qubin (GB7 acupoints treated once a day for 30 minutes. In the DAPT group, modeled rats had 0.15 μg/mL DAPT solution (10 mL infused into the brain. Immunohistochemistry and western blot results showed that acupuncture effectively inhibits Notch1 and Hes1 protein expression in rat basal ganglia. These inhibitory effects were identical to DAPT, a Notch signaling pathway inhibitor. Our results suggest that acupuncture has a neuroprotective effect on cerebral hemorrhage by inhibiting Notch-Hes signaling pathway transduction in rat basal ganglia after cerebral hemorrhage.

  7. Global exponential stability and dissipativity of generalized neural networks with time-varying delay signals.

    Science.gov (United States)

    Manivannan, R; Samidurai, R; Cao, Jinde; Alsaedi, Ahmed; Alsaadi, Fuad E

    2017-03-01

    This paper investigates the problems of exponential stability and dissipativity of generalized neural networks (GNNs) with time-varying delay signals. By constructing a novel Lyapunov-Krasovskii functionals (LKFs) with triple integral terms that contain more advantages of the state vectors of the neural networks, and the upper bound on the time-varying delay signals are formulated. We employ a new integral inequality technique (IIT), free-matrix-based (FMB) integral inequality approach, and Wirtinger double integral inequality (WDII) technique together with the reciprocally convex combination (RCC) approach to bound the time derivative of the LKFs. An improved exponential stability and strictly (Q,S,R)-γ-dissipative conditions of the addressed systems are represented by the linear matrix inequalities (LMIs). Finally, four interesting numerical examples are developed to verify the usefulness of the proposed method with a practical application to a biological network. Copyright © 2016 Elsevier Ltd. All rights reserved.

  8. Cortical Dipole Imaging for Multiple Signal Sources Considering Time-Varying Non-Uniform Noise

    Science.gov (United States)

    Hori, Junichi; Watanabe, Yoshiki

    Cortical dipole imaging is one of the spatial enhancement techniques from the scalp electroencephalogram. We investigated the dipole imaging for multiple signal sources under time-varying non-uniform noise conditions. The effects of incorporating statistical information of noise into the spatiotemporal inverse filter were examined by computer simulations and experimental studies in three sphere volume conductor model. The parametric projection filter that incorporated with noise covariance was applied to the inverse problem of EEG measurements. The noise covariance matrix was estimated by applying independent component analysis to the scalp potentials. The spatial filter was expanded to apply to the time-varying non-uniform noise conditions such as eye blink artifact. Moreover, multiple dipole distributions were introduced to extract and to visualize individual signal sources. The proposed imaging technique was applied to human experimental data of visual evoked potentials. We obtained reasonable results that coincide to physiological knowledge.

  9. Measuring time-varying information flow in scalp EEG signals: Orthogonalized partial directed coherence

    OpenAIRE

    Omidvarnia, Amir; Azemi, Ghasem; Boashash, Boualem; Otoole, John M.; Colditz, Paul B.; Vanhatalo, Sampsa

    2014-01-01

    This study aimed to develop a time-frequency method for measuring directional interactions over time and frequency from scalp-recorded electroencephalographic (EEG) signals in a way that is less affected by volume conduction and amplitude scaling. We modified the time-varying generalized partial directed coherence (tv-gPDC) method, by orthogonalization of the strictly causal multivariate autoregressive model coefficients, to minimize the effect of mutual sources. The novel measure, generalize...

  10. LPL gene expression is associated with poor prognosis in CLL and closely related to NOTCH1 mutations

    DEFF Research Database (Denmark)

    Kristensen, Louise; Kielsgaard Kristensen, Thomas; Abildgaard, Niels

    2016-01-01

    Chronic lymphocytic leukemia is a heterogeneous yet incurable disease. Whole genome and - exome sequencing studies have revealed recurrently occurring somatic mutations in some genes. Several other prognostic markers have previously been tested for their prognostic value in CLL. LPL is among...... these markers. AIM: To evaluate LPL gene expression together with the well-established prognostic markers of CLL and investigate correlations with more recently identified prognostic markers, NOTCH1 and TP53 mutations. METHODS: On 149 patients LPL gene expression was analyzed by real-time RT-PCR. Exon 34...... and new prognostic markers, 3 out of 4 patients, who received treatment within 24 months after diagnosis, were LPL+ (p=0.03). There was a strong correlation between NOTCH1 mutation and LPL+ (p=0.005). The unfavorable prognosis of LPL+ was maintained in CLL with wild-type NOTCH1. CONCLUSIONS: NOTCH1...

  11. Illegitimate V(D)J recombination-mediated deletions in Notch1 and Bcl11b are not sufficient for extensive clonal expansion and show minimal age or sex bias in frequency or junctional processing

    Energy Technology Data Exchange (ETDEWEB)

    Champagne, Devin P., E-mail: devin.champagne@uvm.edu; Shockett, Penny E., E-mail: pshockett@selu.edu

    2014-03-15

    Highlights: • Examines illegitimate V(D)J deletion junctions in Notch1 and Bcl11b. • Suggests little influence of deletions alone on clonal outgrowth in wild-type mice. • No age or sex biases in frequency, clonality, or junctional processing observed. • Contrasts with previous results at TCRβ and HPRT1 loci. • Deletions in Bcl11b may be tolerated more easily than those in Notch1. - Abstract: Illegitimate V(D)J recombination at oncogenes and tumor suppressor genes is implicated in formation of several T cell malignancies. Notch1 and Bcl11b, genes involved in developing T cell specification, selection, proliferation, and survival, were previously shown to contain hotspots for deletional illegitimate V(D)J recombination associated with radiation-induced thymic lymphoma. Interestingly, these deletions were also observed in wild-type animals. In this study, we conducted frequency, clonality, and junctional processing analyses of Notch1 and Bcl11b deletions during mouse development and compared results to published analyses of authentic V(D)J rearrangements at the T cell receptor beta (TCRβ) locus and illegitimate V(D)J deletions observed at the human, nonimmune HPRT1 locus not involved in T cell malignancies. We detect deletions in Notch1 and Bcl11b in thymic and splenic T cell populations, consistent with cells bearing deletions in the circulating lymphocyte pool. Deletions in thymus can occur in utero, increase in frequency between fetal and postnatal stages, are detected at all ages examined between fetal and 7 months, exhibit only limited clonality (contrasting with previous results in radiation-sensitive mouse strains), and consistent with previous reports are more frequent in Bcl11b, partially explained by relatively high Recombination Signal Information Content (RIC) scores. Deletion junctions in Bcl11b exhibit greater germline nucleotide loss, while in Notch1 palindromic (P) nucleotides are more abundant, although average P nucleotide length is

  12. Cortical signal-in-noise coding varies by noise type, signal-to-noise ratio, age, and hearing status.

    Science.gov (United States)

    Maamor, Nashrah; Billings, Curtis J

    2017-01-01

    The purpose of this study was to determine the effects of noise type, signal-to-noise ratio (SNR), age, and hearing status on cortical auditory evoked potentials (CAEPs) to speech sounds. This helps to explain the hearing-in-noise difficulties often seen in the aging and hearing impaired population. Continuous, modulated, and babble noise types were presented at varying SNRs to 30 individuals divided into three groups according to age and hearing status. Significant main effects of noise type, SNR, and group were found. Interaction effects revealed that the SNR effect varies as a function of noise type and is most systematic for continuous noise. Effects of age and hearing loss were limited to CAEP latency and were differentially modulated by energetic and informational-like masking. It is clear that the spectrotemporal characteristics of signals and noises play an important role in determining the morphology of neural responses. Participant factors such as age and hearing status, also play an important role in determining the brain's response to complex auditory stimuli and contribute to the ability to listen in noise. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  13. Role of Notch-1 signaling in ethanol induced PC12 apoptosis

    African Journals Online (AJOL)

    DR. NJ TONUKARI

    2012-04-17

    Apr 17, 2012 ... large portion of our aging population. Neuronal cell apoptosis may be a contributing ... molecules related to the Notch pathway have been impli- cated in several syndromes. Alagille syndrome ..... expression in aging and neurodegenerative disorders associated with oxidative stress: a nutritional approach.

  14. Function of Integrin-Linked Kinase in Modulating the Stemness of IL-6–Abundant Breast Cancer Cells by Regulating γ-Secretase–Mediated Notch1 Activation in Caveolae

    Directory of Open Access Journals (Sweden)

    En-Chi Hsu

    2015-06-01

    Full Text Available Interleukin-6 (IL-6 and Notch signaling are important regulators of breast cancer stem cells (CSCs, which drive the malignant phenotype through self-renewal, differentiation, and development of therapeutic resistance. We investigated the role of integrin-linked kinase (ILK in regulating IL-6–driven Notch1 activation and the ability to target breast CSCs through ILK inhibition. Ectopic expression/short hairpin RNA-mediated knockdown of ILK, pharmacological inhibition of ILK with the small molecule T315, Western blot analysis, immunofluorescence, and luciferase reporter assays were used to evaluate the regulation of IL-6–driven Notch1 activation by ILK in IL-6–producing triple-negative breast cancer cell lines (MDA-MB-231, SUM-159 and in MCF-7 and MCF-7IL-6 cells. The effects of ILK on γ-secretase complex assembly and cellular localization were determined by immunofluorescence, Western blots of membrane fractions, and immunoprecipitation. In vivo effects of T315-induced ILK inhibition on CSCs in SUM-159 xenograft models were assessed by mammosphere assays, flow cytometry, and tumorigenicity assays. Results show that the genetic knockdown or pharmacological inhibition of ILK suppressed Notch1 activation and the abundance of the γ-secretase components presenilin-1, nicastrin, and presenilin enhancer 2 at the posttranscriptional level via inhibition of caveolin-1-dependent membrane assembly of the γ-secretase complex. Accordingly, knockdown of ILK inhibited breast CSC-like properties in vitro and the breast CSC subpopulation in vivo in xenograft tumor models. Based on these findings, we propose a novel function of ILK in regulating γ-secretase–mediated Notch1 activation, which suggests the targeting of ILK as a therapeutic approach to suppress IL-6–induced breast CSCs.

  15. The non-canonical NOTCH1 ligand Delta-like 1 homolog (DLK1) self interacts in mammals

    DEFF Research Database (Denmark)

    Traustadóttir, Gunnhildur Ásta; Jensen, Charlotte Harken; Garcia Ramirez, Jose Javier

    2017-01-01

    data suggest that DLK1 interacts with itself through EGF domain 4 and 5, which is distinct from the recently described NOTCH1-DLK1 interaction, which occurs between EGF domain 5 and 6. This opens up the possibility that Notch independent mechanisms like the DLK1-DLK1 interaction may modulate the non...

  16. Cardiovascular malformations caused by NOTCH1 mutations do not keep left : data on 428 probands with left-sided CHD and their families

    NARCIS (Netherlands)

    Kerstjens-Frederikse, Wilhelmina S; van de Laar, Ingrid M B H; Vos, Yvonne J; Verhagen, Judith M A; Berger, Rolf M F; Lichtenbelt, Klaske D; Klein Wassink-Ruiter, Jolien S; van der Zwaag, Paul A; du Marchie Sarvaas, Gideon J; Bergman, Klasien A; Bilardo, Catia M; Roos-Hesselink, Jolien W; Janssen, Johan H P; Frohn-Mulder, Ingrid M; van Spaendonck-Zwarts, Karin Y; van Melle, Joost P; Hofstra, Robert M W; Wessels, M W

    2016-01-01

    PURPOSE: We aimed to determine the prevalence and phenotypic spectrum of NOTCH1 mutations in left-sided congenital heart disease (LS-CHD). LS-CHD includes aortic valve stenosis, a bicuspid aortic valve, coarctation of the aorta, and hypoplastic left heart syndrome. METHODS: NOTCH1 was screened for

  17. Cardiovascular malformations caused by NOTCH1 mutations do not keep left : data on 428 probands with left-sided CHD and their families

    NARCIS (Netherlands)

    Kerstjens-Frederikse, Wilhelmina S.; van de Laar, Ingrid M. B. H.; Vos, Yvonne J.; Verhagen, Judith M. A.; Berger, Rolf M. F.; Lichtenbelt, Klaske D.; Wassink-Ruiter, Jolien S. Klein; van der Zwaag, Paul A.; Sarvaas, Gideon J. du Marchie; Bergman, Klasien A.; Bilardo, Catia M.; Roos-Hesselink, Jolien W.; Janssen, Johan H. P.; Frohn-Mulder, Ingrid M.; van Spaendonck-Zwarts, Karin Y.; Melle, van Joost P.; Hofstra, Robert M. W.; Wessels, M. W.

    Purpose: We aimed to determine the prevalence and phenotypic spectrum of NOTCH1 mutations in left-sided congenital heart disease (LS-CHD). LS-CHD includes aortic valve stenosis, a bicuspid aortic valve, coarctation of the aorta, and hypoplastic left heart syndrome. Methods: NOTCH1 was screened for

  18. Clinical impact of de-regulated Notch-1 and Notch-3 in the development and progression of HPV-associated different histological subtypes of precancerous and cancerous lesions of human uterine cervix.

    Directory of Open Access Journals (Sweden)

    Richa Tripathi

    Full Text Available Cervical cancer is the leading cause of cancer related deaths among women in India. Limited reports are available for Notch-1 and Notch-3 protein in cervical carcinoma, which play crucial role in cell proliferation, differentiation, and apoptosis.This study was designed to evaluate the role of Notch-1 and Notch-3 with context to HPV infection in cervical carcinoma. A total of 168 tissue biopsy samples comprising of tumor specimens (n = 98, precancer (n = 30 and non-neoplastic cervical tissues (n = 40 were screened for HPV infection by PCR and expression of Notch-1 and Notch-3 protein by Immunohistochemistry and Immunoblotting.80% (24/30 were found to be positive for HPV in precancer and 86.7% (85/98 in cancer patients. Notch-1 expression of precancer and cancer cases was found to be significantly down-regulated with severity of disease in nuclear (3.43±0.29; 2.04±0.19, p = 0.0001, p = 0.0001 and cytoplasm (3.07±0.29; 2.29±0.17, p = 0.0001, p = 0.0001 obtained from different stages as compared to normal cervix tissue (5.40±0.19, 4.97±0.15; p<0.001; p<0.001. However, Notch-3 expression of above cases was significantly up-regulated with severity of disease and showed intense nuclear (4.17±0.39; 4.74±0.18, p = 0.0001, p = 0.0001 and cytoplasm (3.67±0.36; 4.48±0.18, p = 0.0001, p = 0.0001 of different stages as compared to normal cervix tissue (0.95±0.20, 0.70±0.20; p<0.001; p<0.001 respectively.These findings suggest that Notch-1 and Notch-3 may play an important role with synergistic effect of HPV in regulating development and proliferation of cervical cancer through the deregulation of Notch signalling. This study also shows the clinical utility of both proteins which may be used as predictable biomarkers in diagnosing different histological sub-types of HPV associated cervical cancer. Nevertheless, abnormal activation of this pathway may provide legitimate targets for cervical cancer therapy.

  19. Fringe-mediated extension of O-linked fucose in the ligand-binding region of Notch1 increases binding to mammalian Notch ligands.

    Science.gov (United States)

    Taylor, Paul; Takeuchi, Hideyuki; Sheppard, Devon; Chillakuri, Chandramouli; Lea, Susan M; Haltiwanger, Robert S; Handford, Penny A

    2014-05-20

    The Notch signaling pathway is essential for many aspects of development, cell fate determination, and tissue homeostasis. Notch signaling can be modulated by posttranslational modifications to the Notch receptor, which are known to alter both ligand binding and receptor activation. We have modified the ligand-binding region (EGF domains 11-13) of human Notch1 (hN1) with O-fucose and O-glucose glycans and shown by flow cytometry and surface plasmon resonance that the Fringe-catalyzed addition of GlcNAc to the O-fucose at T466 in EGF12 substantially increases binding to Jagged1 and Delta-like 1 (DLL1) ligands. We have subsequently determined the crystal structures of EGF domains 11-13 of hN1 modified with either the O-fucose monosaccharide or the GlcNAc-fucose disaccharide at T466 of EGF12 and observed no change in backbone structure for each variant. Collectively, these data demonstrate a role for GlcNAc in modulating the ligand-binding site in hN1 EGF12, resulting in an increased affinity of this region for ligands Jagged1 and DLL1. We propose that this finding explains the Fringe-catalyzed enhancement of Notch-Delta signaling observed in flies and humans, but suggest that the inhibitory effect of Fringe on Jagged/Serrate mediated signaling involves other regions of Notch.

  20. The internal state of medium spiny neurons varies in response to different input signals

    Directory of Open Access Journals (Sweden)

    Miller Gary W

    2010-03-01

    Full Text Available Abstract Background Parkinson's disease, schizophrenia, Huntington's chorea and drug addiction are manifestations of malfunctioning neurons within the striatum region at the base of the human forebrain. A key component of these neurons is the protein DARPP-32, which receives and processes various types of dopamine and glutamate inputs and translates them into specific biochemical, cellular, physiological, and behavioral responses. DARPP-32's unique capacity of faithfully converting distinct neurotransmitter signals into appropriate responses is achieved through a complex phosphorylation-dephosphorylation system that evades intuition and predictability. Results To gain deeper insights into the functioning of the DARPP-32 signal transduction system, we developed a dynamic model that is robust and consistent with available clinical, pharmacological, and biological observations. Upon validation, the model was first used to explore how different input signal scenarios are processed by DARPP-32 and translated into distinct static and dynamic responses. Secondly, a comprehensive perturbation analysis identified the specific role of each component on the system's signal transduction ability. Conclusions Our study investigated the effects of various patterns of neurotransmission on signal integration and interpretation by DARPP-32 and showed that the DARPP-32 system has the capability of discerning surprisingly many neurotransmission scenarios. We also screened out potential mechanisms underlying this capability of the DARPP-32 system. This type of insight deepens our understanding of neuronal signal transduction in normal medium spiny neurons, sheds light on neurological disorders associated with the striatum, and might aid the search for intervention targets in neurological diseases and drug addiction.

  1. MicroRNA-101 regulates T-cell acute lymphoblastic leukemia progression and chemotherapeutic sensitivity by targeting Notch1.

    Science.gov (United States)

    Qian, Lu; Zhang, Wanggang; Lei, Bo; He, Aili; Ye, Lianhong; Li, Xingzhou; Dong, Xin

    2016-11-01

    The present study aimed to investigate the role of microRNA (miR)-101 in acute lymphoblastic leukemia progression and chemoresistance. Furthermore, a novel target gene of miR-101 was identified. Here, we confirmed that miR-101 was significantly downregulated in the blood samples of patients with T-cell acute lymphoblastic leukemia (T-ALL) compared with the healthy controls, as determined by reverse transcription quantitative polymerase chain reaction (RTqPCR) analysis. The in vitro experiments demonstrated that miR-101 significantly repressed the proliferation and invasion, and induced potent apoptosis in Jurkat cells, as determined by CCK-8, flow cytometer and cell invasion assays. Luciferase assay confirmed that Notch1 was a target gene of miR-101, and western blotting showed that miR-101 suppressed the expression of Notch1 at the protein level. Moreover, functional restoration assays revealed that Notch1 mediates the effects of miR-101 on Jurkat cell proliferation, apoptosis and invasion. miR-101 enhanced the sensitivity of Jurkat cells to the chemotherapeutic agent adriamycin. Taken together, our results show for the first time that miR-101 acts as a tumor suppressor in T-cell acute lymphoblastic leukaemia and it could enhance chemotherapeutic sensitivity. Furthermore, Notch1 was identified to be a novel target of miR-101. This study indicates that miR-101 may represent a potential therapeutic target for T-cell acute lymphoblastic leukemia intervention.

  2. Lysyl oxidase-like 2 represses Notch1 expression in the skin to promote squamous cell carcinoma progression

    Science.gov (United States)

    Martin, Alberto; Salvador, Fernando; Moreno-Bueno, Gema; Floristán, Alfredo; Ruiz-Herguido, Cristina; Cuevas, Eva P; Morales, Saleta; Santos, Vanesa; Csiszar, Katalin; Dubus, Pierre; Haigh, Jody J; Bigas, Anna; Portillo, Francisco; Cano, Amparo

    2015-01-01

    Lysyl oxidase-like 2 (LOXL2) is involved in a wide range of physiological and pathological processes, including fibrosis and tumor progression, implicating intracellular and extracellular functions. To explore the specific in vivo role of LOXL2 in physiological and tumor contexts, we generated conditional gain- and loss-of-function mouse models. Germ-line deletion of Loxl2 promotes lethality in half of newborn mice mainly associated to congenital heart defects, while Loxl2 overexpression triggers male sterility due to epididymal dysfunction caused by epithelial disorganization, fibrosis and acute inflammation. Remarkably, when challenged to chemical skin carcinogenesis, Loxl2-overexpressing mice increased tumor burden and malignant progression, while Loxl2-deficient mice exhibit the opposite phenotypes. Loxl2 levels in premalignant tumors negatively correlate with expression of epidermal differentiation markers and components of the Notch1 pathway. We show that LOXL2 is a direct repressor of NOTCH1. Additionally, we identify an exclusive expression pattern between LOXL2 and members of the canonical NOTCH1 pathway in human HNSCC. Our data identify for the first time novel LOXL2 roles in tissue homeostasis and support it as a target for SCC therapy. PMID:25759215

  3. High expression of C-X-C chemokine receptor 4 and Notch1 is predictive of lymphovascular invasion and poor prognosis in lung adenocarcinoma.

    Science.gov (United States)

    Cong, Zhuangzhuang; Wu, Haiwei; Guo, Zhong; Qin, Tao; Xu, Yang; Jing, Hua; Wang, Yanqing; Shen, Yi

    2017-06-01

    C-X-C chemokine receptor 4 and Notch1 have been shown to play oncogenic role individually. This study aimed to determine the combinatorial role of C-X-C chemokine receptor 4 and Notch1 in lung adenocarcinoma. Expression of C-X-C chemokine receptor 4 and Notch1 was detected in resected tumor samples from 185 patients with lung adenocarcinoma at stage I-IIIa by immunohistochemistry. Correlations of their immunoscores with clinicopathological characteristics and disease-specific survival were retrospectively investigated. A three-dimensional capillary-like sprouting model was established to assess the effects of C-X-C chemokine receptor 4 and Notch1 on angiogenesis in vitro. The results revealed that expression of C-X-C chemokine receptor 4 and Notch1 was elevated in lung adenocarcinoma tissues. The high co-expression of C-X-C chemokine receptor 4 and Notch1 was significantly correlated with tumor size, tumor status, nodal status, tumor stage, and lymphovascular invasion, as well as decreased disease-specific survival. Multivariate analysis showed that lymphovascular invasion (hazard ratio: 0.205, 95% confidence interval: 0.086-0.491, p lung adenocarcinoma. Furthermore, Notch1 enhanced the effects of C-X-C chemokine receptor 4 to promote angiogenesis by regulating Flt1 and Flt4 in vitro. In conclusion, co-expression of C-X-C chemokine receptor 4 and Notch1 is associated with tumor progression and lymphovascular invasion and is an independent indicator of poor survival in lung adenocarcinoma. In lung adenocarcinoma patients with high C-X-C chemokine receptor 4 and Notch1 expression, simultaneous inhibition of both factors might be an effective treatment strategy.

  4. High Efficiency, High Linearity, Switch Mode Power Amplifiers for Varying envelop Signal Applications

    DEFF Research Database (Denmark)

    Tong, Tian; Sira, Daniel; Nielsen, Michael

    2009-01-01

    using switch-mode power amplifier aided by various linearization techniques can present a feasible way to achieve both high linearity and high power efficiency. In this paper two different implementations of the switch-mode power amplifier a re p resented for varying envelop applications: the RF pulse...

  5. Signaling Responses After Varying Sequencing of Strength and Endurance Training in a Fed State.

    Science.gov (United States)

    Jones, Thomas W; Walshe, Ian H; Hamilton, David L; Howatson, Glyn; Russell, Mark; Price, Oliver J; Gibson, Alan St Clair; French, Duncan N

    2016-10-01

    To compare anabolic signaling responses to differing sequences of concurrent strength and endurance training in a fed state. Eighteen resistance-trained men were randomly assigned to the following experimental conditions: strength training (ST), strength followed by endurance training (ST-END), or endurance followed by strength training (END-ST). Muscle tissue samples were taken from the vastus lateralis before each exercise protocol, on cessation of exercise, and 1 h after cessation of strength training. Tissue was analyzed for total and phosphorylated (p-) signaling proteins linked to the mTOR and AMPK networks. Strength-training performance was similar between ST, ST-END, and END-ST. p-S6k1 was elevated from baseline 1 h posttraining in ST and ST-END (both P endurance training is most favorable in promoting anabolic signaling. In the case of the current study an acute bout of concurrent training of differing sequences elicited similar responses of the AMPK and mTOR networks.

  6. Robust Exponential Stability for Uncertain Discrete-Time Switched Systems with Interval Time-Varying Delay through a Switching Signal

    Directory of Open Access Journals (Sweden)

    Jenq-Der Chen

    2014-12-01

    Full Text Available This paper deals with the switching signal design to robust exponential stability for uncertain discrete-time switched systems with interval time-varying delay. The lower and upper bounds of the time-varying delay are assumed to be known. By construction of a new Lyapunov-Krasovskii functional and employing linear matrix inequality, some novel sufficient conditions are proposed to guarantee the global exponential stability for such system with parametric perturbations by using a switching signal. In addition, some nonnegative inequalities are used to provide additional degrees of freedom and reduce the conservativeness of systems. Finally, some numerical examples are given to illustrate performance of the proposed design methods.

  7. EXPRESIÓN DE LOS GENES Serrate1 Y Notch1 DURANTE EL DESARROLLO DEL TERCIO MEDIO FACIAL DEL EMBRIÓN DE POLLO

    Directory of Open Access Journals (Sweden)

    Daniel Mauricio Meza Lasso

    2015-11-01

    Full Text Available RESUMENLa vía de señalización Notch se caracteriza por mediar la comunicación célula-célula, regulando diferentes procesos celulares como proliferación, apoptosis y definición del destino celular. Esta vía ha sido implicada en el desarrollo de estructuras craneofaciales como paladar, diente y bóveda craneal. El objetivo de esta investigación fue identificar los patrones de expresión de los genes componentes de la vía Notch, Serrate1 y Notch1, durante el desarrollo del tercio medio facial. Se utilizaron embriones de pollo (Gallus gallus seleccionados de acuerdo a los criterios de Hamilton y Hamburger y sobre los cuales se realizó hibridación in situ con ribosondas marcadas con Digoxigenina (DIG, para luego ser detectadas con anticuerpos Anti-Dig. Los resultados mostraron expresión de los genes evaluados, en las prominencias maxilares (pmx y frontonasal (pfn durante el desarrollo del tercio medio facial. Estos resultados sugieren una probable participación de la vía Notch a través de estos genes, en los diferentes procesos celulares que determinan la morfogénesis y el desarrollo del tercio medio facial.ABSTRACTThe Notch signaling pathway is characterized by mediate cell-cell communication, regulating different cellular processes as proliferation, apoptosis and cell fate definition. This pathway has been implicated in craniofacial structures development as palate, teeth and cranial vault. The objective of this research was to identify the genes expression patterns of some Notch signaling pathway components, Serrate1 and Notch1, during the midface development. It was used chicken embryos (Gallus gallus selected according to Hamilton and Hamburger criteria. We performed in situ hybridization with Digoxigenin (DIG-labeled riboprobes and detected with the antibody Anti-Dig. The results showed the expression of the evaluated genes in the maxillary (pmx and frontonasal (pfn prominences during the midface development. These results

  8. Improved exponential convergence result for generalized neural networks including interval time-varying delayed signals.

    Science.gov (United States)

    Rajchakit, G; Saravanakumar, R; Ahn, Choon Ki; Karimi, Hamid Reza

    2017-02-01

    This article examines the exponential stability analysis problem of generalized neural networks (GNNs) including interval time-varying delayed states. A new improved exponential stability criterion is presented by establishing a proper Lyapunov-Krasovskii functional (LKF) and employing new analysis theory. The improved reciprocally convex combination (RCC) and weighted integral inequality (WII) techniques are utilized to obtain new sufficient conditions to ascertain the exponential stability result of such delayed GNNs. The superiority of the obtained results is clearly demonstrated by numerical examples. Copyright © 2016 Elsevier Ltd. All rights reserved.

  9. Effects of Varying Gravity Levels on fNIRS Headgear Performance and Signal Recovery

    Science.gov (United States)

    Mackey, Jeffrey R.; Harrivel, Angela R.; Adamovsky, Grigory; Lewandowski, Beth E.; Gotti, Daniel J.; Tin, Padetha; Floyd, Bertram M.

    2013-01-01

    This paper reviews the effects of varying gravitational levels on functional Near-Infrared Spectroscopy (fNIRS) headgear. The fNIRS systems quantify neural activations in the cortex by measuring hemoglobin concentration changes via optical intensity. Such activation measurement allows for the detection of cognitive state, which can be important for emotional stability, human performance and vigilance optimization, and the detection of hazardous operator state. The technique depends on coupling between the fNIRS probe and users skin. Such coupling may be highly susceptible to motion if probe-containing headgear designs are not adequately tested. The lack of reliable and self-applicable headgear robust to the influence of motion artifact currently inhibits its operational use in aerospace environments. Both NASAs Aviation Safety and Human Research Programs are interested in this technology as a method of monitoring cognitive state of pilots and crew.

  10. Securing OFDM over Wireless Time-Varying Channels Using Subcarrier Overloading with Joint Signal Constellations

    Directory of Open Access Journals (Sweden)

    Gill R. Tsouri

    2009-01-01

    Full Text Available A method of overloading subcarriers by multiple transmitters to secure OFDM in wireless time-varying channels is proposed and analyzed. The method is based on reverse piloting, superposition modulation, and joint decoding. It makes use of channel randomness, reciprocity, and fast decorrelation in space to secure OFDM with low overheads on encryption, decryption, and key distribution. These properties make it a good alternative to traditional software-based information security algorithms in systems where the costs associated with such algorithms are an implementation obstacle. A necessary and sufficient condition for achieving information theoretic security in accordance with channel and system parameters is derived. Security by complexity is assessed for cases where the condition for information theoretic security is not satisfied. In addition, practical means for implementing the method are derived including generating robust joint constellations, decoding data with low complexity, and mitigating the effects of imperfections due to mobility, power control errors, and synchronization errors.

  11. Matching synchrosqueezing transform: A useful tool for characterizing signals with fast varying instantaneous frequency and application to machine fault diagnosis

    Science.gov (United States)

    Wang, Shibin; Chen, Xuefeng; Selesnick, Ivan W.; Guo, Yanjie; Tong, Chaowei; Zhang, Xingwu

    2018-02-01

    Synchrosqueezing transform (SST) can effectively improve the readability of the time-frequency (TF) representation (TFR) of nonstationary signals composed of multiple components with slow varying instantaneous frequency (IF). However, for signals composed of multiple components with fast varying IF, SST still suffers from TF blurs. In this paper, we introduce a time-frequency analysis (TFA) method called matching synchrosqueezing transform (MSST) that achieves a highly concentrated TF representation comparable to the standard TF reassignment methods (STFRM), even for signals with fast varying IF, and furthermore, MSST retains the reconstruction benefit of SST. MSST captures the philosophy of STFRM to simultaneously consider time and frequency variables, and incorporates three estimators (i.e., the IF estimator, the group delay estimator, and a chirp-rate estimator) into a comprehensive and accurate IF estimator. In this paper, we first introduce the motivation of MSST with three heuristic examples. Then we introduce a precise mathematical definition of a class of chirp-like intrinsic-mode-type functions that locally can be viewed as a sum of a reasonably small number of approximate chirp signals, and we prove that MSST does indeed succeed in estimating chirp-rate and IF of arbitrary functions in this class and succeed in decomposing these functions. Furthermore, we describe an efficient numerical algorithm for the practical implementation of the MSST, and we provide an adaptive IF extraction method for MSST reconstruction. Finally, we verify the effectiveness of the MSST in practical applications for machine fault diagnosis, including gearbox fault diagnosis for a wind turbine in variable speed conditions and rotor rub-impact fault diagnosis for a dual-rotor turbofan engine.

  12. Physiological Signal Analysis for Evaluating Flow during Playing of Computer Games of Varying Difficulty

    Directory of Open Access Journals (Sweden)

    Yu Tian

    2017-07-01

    Full Text Available Flow is the experience of effortless attention, reduced self-consciousness, and a deep sense of control that typically occurs during the optimal performance of challenging tasks. On the basis of the person–artifact–task model, we selected computer games (tasks with varying levels of difficulty (difficult, medium, and easy and shyness (personality as flow precursors to study the physiological activity of users in a flow state. Cardiac and respiratory activity and mean changes in skin conductance (SC were measured continuously while the participants (n = 40 played the games. Moreover, the associations between self-reported psychological flow and physiological measures were investigated through a series of repeated-measures analyses. The results showed that the flow experience is related to a faster respiratory rate, deeper respiration, moderate heart rate (HR, moderate HR variability, and moderate SC. The main effect of shyness was non-significant, whereas the interaction of shyness and difficulty influenced the flow experience. These findings are discussed in relation to current models of arousal and valence. The results indicate that the flow state is a state of moderate mental effort that arises through the increased parasympathetic modulation of sympathetic activity.

  13. Physiological Signal Analysis for Evaluating Flow during Playing of Computer Games of Varying Difficulty.

    Science.gov (United States)

    Tian, Yu; Bian, Yulong; Han, Piguo; Wang, Peng; Gao, Fengqiang; Chen, Yingmin

    2017-01-01

    Flow is the experience of effortless attention, reduced self-consciousness, and a deep sense of control that typically occurs during the optimal performance of challenging tasks. On the basis of the person-artifact-task model, we selected computer games (tasks) with varying levels of difficulty (difficult, medium, and easy) and shyness (personality) as flow precursors to study the physiological activity of users in a flow state. Cardiac and respiratory activity and mean changes in skin conductance (SC) were measured continuously while the participants (n = 40) played the games. Moreover, the associations between self-reported psychological flow and physiological measures were investigated through a series of repeated-measures analyses. The results showed that the flow experience is related to a faster respiratory rate, deeper respiration, moderate heart rate (HR), moderate HR variability, and moderate SC. The main effect of shyness was non-significant, whereas the interaction of shyness and difficulty influenced the flow experience. These findings are discussed in relation to current models of arousal and valence. The results indicate that the flow state is a state of moderate mental effort that arises through the increased parasympathetic modulation of sympathetic activity.

  14. ZigBee’s Received Signal Strength and Latency Evaluation under Varying Environments

    Directory of Open Access Journals (Sweden)

    H. H. R. Sherazi

    2016-01-01

    Full Text Available Being self-configured, self-organized, and self-healing low power technology, ZigBee has obtained significant attention in last few years for achieving ubiquitous communication among various devices within a Personal Area Network (PAN. Even after a decade of its emergence, it has been well serving the communication needs of numerous modern applications belonging to multiple industries and is still a spotlight for the researchers working on certain aspects to enhance productivity along with a major cost reduction. Despite its robust communication nature, it heavily depends upon the context and is prone to the external effects that may cause a serious threat to prospective applications. This paper presents the novel experimental analysis conducted on real test beds to evaluate the impact of continuously changing communication environment on various parameters, for example, RSSI (Received Signal Strength Indicator and latency in the presence of multiple obstacles that may lead to severe degradation in the overall performance. Eventually, we suggest a suitable frame size for ZigBee based on our results deduced from the experimental study.

  15. Visualizing time: how linguistic metaphors are incorporated into displaying instruments in the process of interpreting time-varying signals

    Science.gov (United States)

    Garcia-Belmonte, Germà

    2017-06-01

    Spatial visualization is a well-established topic of education research that has allowed improving science and engineering students' skills on spatial relations. Connections have been established between visualization as a comprehension tool and instruction in several scientific fields. Learning about dynamic processes mainly relies upon static spatial representations or images. Visualization of time is inherently problematic because time can be conceptualized in terms of two opposite conceptual metaphors based on spatial relations as inferred from conventional linguistic patterns. The situation is particularly demanding when time-varying signals are recorded using displaying electronic instruments, and the image should be properly interpreted. This work deals with the interplay between linguistic metaphors, visual thinking and scientific instrument mediation in the process of interpreting time-varying signals displayed by electronic instruments. The analysis draws on a simplified version of a communication system as example of practical signal recording and image visualization in a physics and engineering laboratory experience. Instrumentation delivers meaningful signal representations because it is designed to incorporate a specific and culturally favored time view. It is suggested that difficulties in interpreting time-varying signals are linked with the existing dual perception of conflicting time metaphors. The activation of specific space-time conceptual mapping might allow for a proper signal interpretation. Instruments play then a central role as visualization mediators by yielding an image that matches specific perception abilities and practical purposes. Here I have identified two ways of understanding time as used in different trajectories through which students are located. Interestingly specific displaying instruments belonging to different cultural traditions incorporate contrasting time views. One of them sees time in terms of a dynamic metaphor

  16. Hepatitis B virus X protein promotes interleukin-7 receptor expression via NF-κB and Notch1 pathway to facilitate proliferation and migration of hepatitis B virus-related hepatoma cells

    Directory of Open Access Journals (Sweden)

    Fanyun Kong

    2016-11-01

    Full Text Available Abstract Background Interleukin-7 receptor (IL-7R is involved in the abnormal function of solid tumors, but the role and regulatory mechanisms of IL-7R in HBV-related hepatocellular carcinoma (HCC are still unclear. Methods Gene and protein expression levels of IL-7R were examined in hepatoma cells transfected with hepatitis B virus (HBV plasmids and in hepatoma cells transfected with the multifunctional nonstructural protein X (HBX. The expression of HBX and IL-7R was measured by immunohistochemical analysis in HBV-related HCC tissues. The role of NF-κB and Notch1 pathways in HBX-mediated expression of IL-7R in hepatoma cells was examined. Activation of IL-7R downstream of intracellular signaling proteins AKT, JNK, STAT5, and the associated molecules CyclinD1 and matrix metalloproteinase-9 (MMP-9, was assessed in HBX-positive cells with or without treatment with IL-7R short hairpin RNA (shRNA. Additionally, the role of IL-7R in HBX-mediated proliferation and migration of hepatoma cells was investigated. Results The expression of IL-7R was increased in hepatoma cells transfected with HBV plasmids; HBX was responsible for the HBV-mediated upregulation of IL-7R. Compared to adjacent tissues, the expression of HBX and IL-7R was increased in HBV-related HCC tissues. Additionally, the relative expression levels of HBX were associated with IL-7R in HBV-related HCC tissues. The activation of NF-κB pathways and expression of Notch1 were increased in hepatoma cells transfected with HBX, and inhibition of NF-κB and Notch1 pathways significantly decreased HBX-mediated expression of IL-7R. The activation of AKT and JNK and the expression of CyclinD1 and MMP-9 were increased in HBX-positive cells. When cells were treated with IL-7R shRNA, the activation of AKT and JNK, as well as the expression of CyclinD1 and MMP-9, were significantly inhibited. Additionally, IL-7R was responsible for HBX-induced proliferation and migration ability of hepatoma cells

  17. Seamless Data-Rate Change Using Punctured Convolutional Codes for a Time-Varying Signal-to-Noise Ratio

    Science.gov (United States)

    Feria, Ying; Cheung, Kar-Ming

    1995-01-01

    In a time-varying signal-to-noise-ratio (SNR) environment, symbol rate is changed to maximize data return. However, the symbol-rate changes may cause the receiver symbol loop to lose lock, thus losing real-time data. We propose an alternate way of varying the data rate in a seamless fashion by puncturing the convolutionally encoded symbol stream and transmitting the punctured encoded symbols with a constant symbol rate. We systematically searched for good puncturing patterns for the Galileo (14,1/4) convolutional code and changed the data rates by using the punctured codes to match the Galileo SNR profile of November 9, 1997. We concluded that this scheme reduces the symbol-rate changes from 9 to 2 and provides a larger data return and a higher symbol SNR during most of the day.

  18. Seamless Data-Rate Change Using Punctured Convolutional Codes for Time-Varying Signal-to-Noise Ratio

    Science.gov (United States)

    Feria, Ying

    1995-01-01

    In a time-varying signal-to-noise (SNR) environment, symbol rate is often changed to maximize ata return. However, the symbol-rate change has some undesirable effects such as changing the ransmission bandwidth and perhaps causing the receiver symbol loop to lose lock temporarily, thus osing some data. In this article, we are proposing an alternate way of varying the data rate without hanging the symbol rate and therefore the transmission bandwidth. The data rate change is achieved n a seamless fashion by puncturing the convolutionally encoded symbol stream to adapt to the hanging SNR environment. We have also derived an exact expression to enumerate the number of nique puncturing patterns. To demonstrate this seamless rate-change capability, we searched for good uncturing patterns for the Galileo (14, 1/4) convolutional code and changed the data rates by using the unctured codes to match the Galileo SNR profile of November 9, 1997.

  19. A Flexible Terminal Approach to Sampled-Data Exponentially Synchronization of Markovian Neural Networks With Time-Varying Delayed Signals.

    Science.gov (United States)

    Cheng, Jun; Park, Ju H; Karimi, Hamid Reza; Shen, Hao

    2017-08-02

    This paper investigates the problem of sampled-data (SD) exponentially synchronization for a class of Markovian neural networks with time-varying delayed signals. Based on the tunable parameter and convex combination computational method, a new approach named flexible terminal approach is proposed to reduce the conservatism of delay-dependent synchronization criteria. The SD subject to stochastic sampling period is introduced to exhibit the general phenomena of reality. Novel exponential synchronization criterion are derived by utilizing uniform Lyapunov-Krasovskii functional and suitable integral inequality. Finally, numerical examples are provided to show the usefulness and advantages of the proposed design procedure.

  20. Nuclear Factor Erythroid 2 Regulates Human HSC Self-Renewal and T Cell Differentiation by Preventing NOTCH1 Activation

    Directory of Open Access Journals (Sweden)

    Alessandro Di Tullio

    2017-07-01

    Full Text Available Nuclear factor erythroid-derived 2 (NF-E2 has been associated with megakaryocyte maturation and platelet production. Recently, an increased in NF-E2 activity has been implicated in myeloproliferative neoplasms. Here, we investigate the role of NF-E2 in normal human hematopoiesis. Knockdown of NF-E2 in the hematopoietic stem and progenitor cells (HSPCs not only reduced the formation of megakaryocytes but also drastically impaired hematopoietic stem cell activity, decreasing human engraftment in immunodeficient (NSG mice. This phenotype is likely to be related to both increased cell proliferation (p21-mediated and reduced Notch1 protein expression, which favors HSPC differentiation over self-renewal. Strikingly, although NF-E2 silencing in HSPCs did not affect their myeloid and B cell differentiation in vivo, it almost abrogated T cell production in primary hosts, as confirmed by in vitro studies. This effect is at least partly due to Notch1 downregulation in NF-E2-silenced HSPCs. Together these data reveal that NF-E2 is an important driver of human hematopoietic stem cell maintenance and T lineage differentiation.

  1. Immunohistochemical expression of p63, epidermal growth factor receptor (EGFR) and notch-1 in radicular cysts, dentigerous cysts and keratocystic odontogenic tumors.

    Science.gov (United States)

    Gonçalves, Cláudia Kallás; Fregnani, Eduardo Rodrigues; Leon, Jorge Esquiche; Silva-Sousa, Yara Teresinha Corrêa; Perez, Danyel Elias da Cruz

    2012-01-01

    The aim of this study was to assess the immunohistochemical expression of p63 protein, epidermal growth factor receptor (EGFR) and Notch-1 in the epithelial lining of radicular cysts (RC), dentigerous cysts (DC) and keratocystic odontogenic tumors (KOT). For this study, 35 RC, 22 DC and 17 KOT were used. The clinical and epidemiological data were collected from the patient charts filed in the Oral Pathology Laboratory, University of Ribeirão Preto, Brazil. Immunohistochemical reactions against the p63, EGFR and Notch-1 were performed in 3-µm-thick histological sections. The slides were evaluated according to the following criteria: negative: 50% of positive cells. Moreover, the intensity of EGFR and Notch-1 expressions was also evaluated. Fisher's exact test and Spearman's correlation coefficients were used for statistical analysis, considering a significance level of 5%. Almost all cases demonstrated p63, EGFR and Notch-1 expressions. The p63 expression was significantly higher in KOT (p<0.001). Positive correlation between these immunomarkers was observed. These findings suggest the participation of p63, EGFR and Notch-1 in the development, maintenance and integrity of cystic odontogenic epithelial lining, favoring lesion persistence. The high expression of p63 in KOT suggests that it may be related to their more aggressive biological behavior and marked tendency to recurrence.

  2. Notch Inhibitor PF-03084014 Inhibits Hepatocellular Carcinoma Growth and Metastasis via Suppression of Cancer Stemness due to Reduced Activation of Notch1-Stat3.

    Science.gov (United States)

    Wu, Chuan Xing; Xu, Aimin; Zhang, Cathy C; Olson, Peter; Chen, Lin; Lee, Terence K; Cheung, Tan To; Lo, Chung Mau; Wang, Xiao Qi

    2017-08-01

    Aberrant activation of the Notch signaling pathway is implicated in many solid tumors, including hepatocellular carcinoma, indicating a potential use of Notch inhibitors for treatment. In this study, we investigated the antitumor and antimetastasis efficacy of the novel Notch inhibitor (γ-secretase inhibitor) PF-03084014 in hepatocellular carcinoma. Hepatocellular carcinoma spherical cells (stem-like cancer cells), a sphere-derived orthotopic tumor model and one patient-derived xenograft (PDX) model were used in our experiment. We demonstrated that PF-03084014 inhibited the self-renewal and proliferation of cancer stem cells. PF-03084014 reduced the hepatocellular carcinoma sphere-derived orthotopic tumor and blocked the hepatocellular carcinoma tumor liver to lung metastasis. We further tested the PF-03084014 in PDX models and confirmed the inhibition tumor growth effect. In addition, a low dose of PF-03084014 induced hepatocellular carcinoma sphere differentiation, resulting in chemosensitization. Antitumor activity was associated with PF-03084014-induced suppression of Notch1 activity, decreased Stat3 activation and phosphorylation of the Akt signaling pathway, and reduced epithelial-mesenchymal transition. These are the key contributors to the maintenance of cancer stemness and the promotion of cancer metastasis. Moreover, the Notch-Stat3 association was implicated in the clinical hepatocellular carcinoma prognosis. Collectively, PF-03084014 revealed antitumor and antimetastatic effects in hepatocellular carcinoma, providing evidence for the potential use of gamma-secretase inhibitors as a therapeutic option for the treatment of hepatocellular carcinoma. Mol Cancer Ther; 16(8); 1531-43. ©2017 AACR. ©2017 American Association for Cancer Research.

  3. LOH at chromosome 9q34.3 and the Notch1 gene methylation are less involved in oral squamous cell carcinomas

    DEFF Research Database (Denmark)

    Gao, Shan; Krogdahl, Annelise; Eiberg, Hans

    2007-01-01

    BACKGROUND: Previous studies of oral carcinomas have shown that both loss of heterozygosity (LOH) and hypermethylation at chromosome 9q33 to 9q34.2 are frequent. The present study investigates the frequency of Notch1 gene methylation and LOH at 9q34.3 region. METHODS: Gene promoter hypermethylation...... of the Notch1 gene was analysed by methylation-specific PCR and LOH was analysed using microsatellite markers. RESULTS: We found LOH at 9q34.3 in three patients and methylation of the Notch1 gene only in two patients with oral carcinoma. CONCLUSION: Comparing with the alterations at 9q33 to 34.2 regions, LOH...

  4. Multifunctional core/shell nanoparticles cross-linked polyetherimide-folic acid as efficient Notch-1 siRNA carrier for targeted killing of breast cancer.

    Science.gov (United States)

    Yang, Hong; Li, Ying; Li, Tingting; Xu, Min; Chen, Yin; Wu, Chunhui; Dang, Xitong; Liu, Yiyao

    2014-11-17

    In gene therapy, how genetic therapeutics can be efficiently and safely delivered into target tissues/cells remains a major obstacle to overcome. To address this issue, nanoparticles consisting of non-covalently coupled polyethyleneimine (PEI) and folic acid (FA) to the magnetic and fluorescent core/shell of Fe3O4@SiO2(FITC) was tested for their ability to deliver Notch-1 shRNA. Our results showed that Fe3O4@SiO2(FITC)/PEI-FA/Notch-1 shRNA nanoparticles are 64 nm in diameter with well dispersed and superparamagnetic. These nanoparticles with on significant cytotoxicity are capable of delivering Notch-1 shRNA into human breast cancer MDA-MB-231 cells with high efficiency while effectively protected shRNA from degradation by exogenous DNaseI and nucleases. Magnetic resonance (MR) imaging and fluorescence microscopy showed significant preferential uptake of Fe3O4@SiO2(FITC)/PEI-FA/Notch-1 shRNA nanocomplex by MDA-MB-231 cells. Transfected MDA-MB-231 cells exhibited significantly decreased expression of Notch-1, inhibited cell proliferation, and increased cell apoptosis, leading to the killing of MDA-MB-231 cells. In light of the magnetic targeting capabilities of Fe3O4@SiO2(FITC)/PEI-FA, our results show that by complexing with a second molecular targeting therapeutic, such as Notch-1 shRNA in this report, Fe3O4@SiO2(FITC)/PEI-FA can be exploited as a novel, non-viral, and concurrent targeting delivery system for targeted gene therapy as well as for MR imaging in cancer diagnosis.

  5. Inhibitory effects of microRNA-34a on proliferation of bladder tumor cell line T24 by targeting Notch1

    Directory of Open Access Journals (Sweden)

    Chao ZHANG

    2012-05-01

    Full Text Available Objective  To explore the correlation between microRNA-34a (miR-34a and Notch1, and evaluate the influence of miR-34a overexpression on proliferation of bladder cancer cell line T24. Methods  Bioinformatics software were used for predicting the binding site of miR-34a and Notch1, and luciferase assay was performed for confirming the direct regulatory relationship between them. miR-34a plasmid was transfected into bladder cancer cell line T24. Notch1 expression was detected by quantitative real-time polymerase chain reaction and Western blotting. Cell proliferation was assayed by 3-(4,5-dimethylthiazol-2-yl-5-(3-carboxymethoxyphenyl-2-(4-sulfophenyl-2H-tetrazolium (MTS assay. Apoptosis and cell cycle were assessed by flow cytometry. Results  Luciferase assays showed that miR-34a transfection significantly down-regulated the normalized Notch1 3'UTR luciferase activity (P=0.006. Transfection of miR-34a reduced the RNA and protein levels of Notch1. Cell proliferation assay revealed that miR-34a transfection suppressed the proliferation of T24 cells in a time-dependent manner (P < 0.001. Ectopic expression of miR-34a caused significant increase of apoptotic cells (P=0.003 and induced cell cycle arrest at G0-G1 phase in T24 cells (P=0.002. Conclusion  Overexpressed miRNA-34a can inhibit proliferation of bladder cancer cells by antagonizing Notch1, thus indicating its tumor-suppressive function in bladder cancer.

  6. Seamless data-range change using punctured convolutional codes for time-varying signal-to-noise ratios

    Science.gov (United States)

    Feria, Y.; Cheung, K.-M.

    1995-01-01

    In a time-varying signal-to-noise ration (SNR) environment, symbol rate is often changed to maximize data return. However, the symbol-rate change has some undesirable effects, such as changing the transmission bandwidth and perhaps causing the receiver symbol loop to lose lock temporarily, thus losing some data. In this article, we are proposing an alternate way of varying the data rate without changing the symbol rate and, therefore, the transmission bandwidth. The data rate change is achieved in a seamless fashion by puncturing the convolutionally encoded symbol stream to adapt to the changing SNR environment. We have also derived an exact expression to enumerate the number of distinct puncturing patterns. To demonstrate this seamless rate change capability, we searched for good puncturing patterns for the Galileo (14,1/4) convolutional code and changed the data rates by using the punctured codes to match the Galileo SNR profile of November 9, 1997. We show that this scheme reduces the symbol-rate changes from nine to two and provides a comparable data return in a day and a higher symbol SNR during most of the day.

  7. ALDH+ tumor-initiating cells exhibiting gain in NOTCH1 gene copy number have enhanced regrowth sensitivity to a γ-secretase inhibitor and irinotecan in colorectal cancer.

    Science.gov (United States)

    Arcaroli, John J; Powell, Rebecca W; Varella-Garcia, Marileila; McManus, Martine; Tan, Aik Choon; Quackenbush, Kevin S; Pitts, Todd M; Gao, Dexiang; Spreafico, Anna; Dasari, Arvind; Touban, Basel M; Messersmith, Wells A

    2012-06-01

    The Notch signaling pathway has been shown to be upregulated in colorectal cancer (CRC) and important for the self-renewal of cancer stem cells. In this study, we evaluated the efficacy of PF-03084014, a γ-secretase inhibitor, in combination with irinotecan to identify the effects of treatment on tumor recurrence and the tumor-initiating population in our CRC preclinical explant model. The combination of PF-03084014 and irinotecan had the greatest effect at reducing tumor growth on four CRC tumors when compared with treatment with PF-03084014 or irinotecan alone. The combination significantly reduced tumor recurrence in two CRC explants (CRC001 and CRC036) after treatment was discontinued. Both of these tumors exhibited elevated baseline levels of Notch pathway activation as well as an increase in NOTCH1 gene copy number when compared with the two CRC explants (CRC026 and CRC027) where tumors reappeared quickly after termination of treatment. Isolation and injection of aldehyde dehydrogenase (ALDH(+) and ALDH(-)) cells in an in vivo explant model demonstrated that the ALDH(+) cell population were tumorigenic. Evaluation of the ALDH(+) cells after 28 days of treatment showed that the combination reduced the ALDH(+) population in the tumors that did not regrow. Furthermore, ALDH(+) cells from CRC001 and CRC027 were injected in vivo and treated immediately for 28 days. Two months after treatment, tumors were evident in the combination treatment group for CRC027 but not for CRC036. These results indicate the combination of PF-03084014 and irinotecan may be effective in reducing tumor recurrence in CRC patients whose tumors exhibit elevated levels of the Notch pathway. Copyright © 2012 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

  8. MicroRNA-34a modulates the Notch signaling pathway in mice with congenital heart disease and its role in heart development.

    Science.gov (United States)

    Wu, Kai-Hong; Xiao, Qian-Ru; Yang, Yu; Xu, Jia-Li; Zhang, Feng; Liu, Chao-Ming; Zhang, Zhao-Ming; Lu, Ying-Qi; Huang, Ning-Ping

    2017-11-22

    The objective of the study was to elucidate the mechanism by which microRNA-34a (miR-34a) influences heart development and participates in the pathogenesis of congenital heart disease (CHD) by targeting NOTCH-1 through the Notch signaling pathway. Forty D7 pregnant mice were recruited for the purposes of the study and served as the CHD (n=20, successfully established as CHD model) and normal (n=20) groups. The positive expression of the NOTCH-1 protein was evaluated by means of immunohistochemistry. Embryonic endocardial cells (ECCs) were assigned into the normal, blank, negative control (NC), miR-34a mimics, miR-34a inhibitors, miR-34a inhibitors+siRNA-NOTCH-1, siRNA-NOTCH-1, miR-34a mimics+NOTCH-1 OE and miR-34a mimics+crispr/cas9 (mutant NOTCH-1) groups. The expressions of miR-34a, NOTCH-1, Jagged1, Hes1, Hey2 and Csx in cardiac tissues and ECCs were determined by both RT-qPCR and western blotting methods. MTT assay and flow cytometry were conducted for cell proliferation and apoptosis measurement. A dual luciferase reporter assay was applied to demonstrate that NOTCH-1 was the target gene of miR-34a. In comparison to the normal group, the expressions of miR-34a, Jagged1, Hes1 and Hey2 displayed up-regulated levels, while the expressions of NOTCH-1 and Csx were down-regulated in the CHD group. Compared with the blank and NC groups, the miR-34a mimics and siRNA-NOTCH-1 groups displayed reduced expressions of NOTCH-1 and Csx as well as a decreased proliferation rate, higher miR-34a, Jagged1, Hes1 and Hey2 expressions and an increased rate of apoptosis; while an reverse trend was observed in the miR-34a inhibitors group. The expressions of MiR-34a recorded increased levels in the miR-34a mimics+NOTCH-1 OE and miR-34a mimics+crispr/cas9 (mutant NOTCH-1) groups, however no changes in the expressions of NOTCH-1, Jagged1, Hes1, Hey2, Csx, as well as cell proliferation and apoptosis were observed when compared to the blank and NC groups. The results of our study

  9. Immunohistochemical expression of p63, epidermal growth factor receptor (EGFR) and notch-1 in radicular cysts, dentigerous cysts and keratocystic odontogenic tumors

    OpenAIRE

    Gonçalves, Cláudia Kallás; Fregnani, Eduardo Rodrigues; Leon, Jorge Esquiche; SILVA-SOUSA, Yara Teresinha Corrêa; Perez, Danyel Elias da Cruz

    2012-01-01

    The aim of this study was to assess the immunohistochemical expression of p63 protein, epidermal growth factor receptor (EGFR) and Notch-1 in the epithelial lining of radicular cysts (RC), dentigerous cysts (DC) and keratocystic odontogenic tumors (KOT). For this study, 35 RC, 22 DC and 17 KOT were used. The clinical and epidemiological data were collected from the patient charts filed in the Oral Pathology Laboratory, University of Ribeirão Preto, Brazil. Immunohistochemical reactions agains...

  10. Utility of LRF/Pokemon and NOTCH1 Protein Expression in the Distinction of Nodular Lymphocyte-Predominant Hodgkin Lymphoma and Classical Hodgkin Lymphoma

    Science.gov (United States)

    Bohn, Olga; Maeda, Takahiro; Filatov, Alexander; Lunardi, Andrea; Pandolfi, Pier Paolo; Teruya-Feldstein, Julie

    2014-01-01

    Classical Hodgkin lymphoma (CHL) and nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) are considered separate entities with different prognosis and treatment. However, morphologic features can be similar and immunohistochemical studies are essential in the distinction; thus, determination of additional biomarkers is of utmost importance. LRF/Pokemon is a protooncogene, an interacting partner co-expressed with BCL6 in germinal centers and highly expressed in diffuse large B-cell lymphoma and follicular lymphoma. Conversely, loss of the LRF gene in mouse hematopoietic stem cells results in complete block of early B cell development with concomitant Notch derepression, indicating its critical role in B versus T cell fate decision at the hematopoietic stem cell stage. For the first time, we show that LRF/Pokemon is predominantly expressed in NLPHL cases as is BCL6 with low to absent NOTCH1 protein expression; while Hodgkin Reed-Sternberg (HRS) cells in CHL show low to absent BCL6 and LRF/Pokemon expression with higher NOTCH1 expression. We illustrate a potential functional interaction between LRF and BCL6 in NLPHL pathogenesis, and differential expression of LRF/Pokemon and NOTCH1 proteins in CHL thus showing differential expression, making for an additional diagnostic marker and therapeutic target. PMID:24326827

  11. Utility of LRF/Pokemon and NOTCH1 protein expression in the distinction between nodular lymphocyte-predominant Hodgkin lymphoma and classical Hodgkin lymphoma.

    Science.gov (United States)

    Bohn, Olga; Maeda, Takahiro; Filatov, Alexander; Lunardi, Andrea; Pandolfi, Pier Paolo; Teruya-Feldstein, Julie

    2014-02-01

    Classical Hodgkin lymphoma (CHL) and nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) are considered separate entities with different prognosis and treatment. However, morphologic features can be similar and immunohistochemical studies are essential in the distinction; thus, determination of additional biomarkers is of utmost importance. LRF/Pokemon is a proto-oncogene, an interacting partner co-expressed with BCL6 in germinal centers and highly expressed in diffuse large B-cell lymphoma and follicular lymphoma. Conversely, loss of the LRF gene in mouse hematopoietic stem cells results in complete block of early B cell development with concomitant Notch de-repression, indicating its critical role in B versus T cell fate decision at the hematopoietic stem cell stage. For the first time, we show that LRF/Pokemon is predominantly expressed in NLPHL cases as is BCL6 with low to absent NOTCH1 protein expression; while Hodgkin Reed-Sternberg (HRS) cells in CHL show low to absent BCL6 and LRF/Pokemon expression with higher NOTCH1 expression. We illustrate a potential functional interaction between LRF and BCL6 in NLPHL pathogenesis, and differential expression of LRF/Pokemon and NOTCH1 proteins in CHL thus showing differential expression, making for an additional diagnostic marker and therapeutic target.

  12. Notch-1 mediated cardiac protection following embryonic and induced pluripotent stem cell transplantation in doxorubicin-induced heart failure.

    Directory of Open Access Journals (Sweden)

    Hilda Merino

    Full Text Available Doxorubicin (DOX, an effective chemotherapeutic drug used in the treatment of various cancers, is limited in its clinical applications due to cardiotoxicity. Recent studies suggest that transplanted adult stem cells inhibit DOX-induced cardiotoxicity. However, the effects of transplanted embryonic stem (ES and induced pluripotent stem (iPS cells are completely unknown in DOX-induced left ventricular dysfunction following myocardial infarction (MI. In brief, C57BL/6 mice were divided into five groups: Sham, DOX-MI, DOX-MI+cell culture (CC media, DOX-MI+ES cells, and DOX-MI+iPS cells. Mice were injected with cumulative dose of 12 mg/kg of DOX and 2 weeks later, MI was induced by coronary artery ligation. Following ligation, 5×10(4 ES or iPS cells were delivered into the peri-infarct region. At day 14 post-MI, echocardiography was performed, mice were sacrificed, and hearts were harvested for further analyses. Our data reveal apoptosis was significantly inhibited in ES and iPS cell transplanted hearts compared with respective controls (DOX-MI+ES: 0.48±0.06% and DOX-MI+iPS: 0.33±0.05% vs.1.04±0.07% and DOX-MI+CC: 0.96±0.21%; p<0.05. Furthermore, a significant increase in levels of Notch-1 (p<0.05, Hes1 (p<0.05, and pAkt (p<0.05 were observed whereas a decrease in the levels of PTEN (p<0.05, a negative regulator of Akt, was evident following stem cell transplantation. Moreover, hearts transplanted with stem cells demonstrated decreased vascular and interstitial fibrosis (p<0.05 as well as MMP-9 expression (p<0.01 compared with controls. Additionally, heart function was significantly improved (p<0.05 in both cell-transplanted groups. In conclusion, our data show that transplantation of ES and iPS cells blunt DOX-induced adverse cardiac remodeling, which is associated with improved cardiac function, and these effects are mediated by the Notch pathway.

  13. A field experiment on microwave forest radiometry: L-band signal behaviour for varying conditions of surface wetness

    DEFF Research Database (Denmark)

    Grant, J. P.; Wigneron, J. P.; Van de Grind, A. A.

    2007-01-01

    France, using a multi-angle L-band (1.4 GHz) radiometer to measure from above the forest at horizontal polarization. At the same time, ground measurements were taken of soil and litter moisture content, while precipitation was also permanently monitored. This experiment was done in the context...... of the upcoming SMOS mission in order to improve our understanding of the behaviour of the L-band signal from forested areas for different wetness conditions and viewing angles. This is especially relevant for solving the problem of heterogeneity since a large fraction of SMOS pixels (~30x30 km²) is partially...... covered by forest. This paper describes the objectives and the overall set-up of the Bray-2004 experiment and shows some first results. The greater part of the horizontally polarized L-band signal is found to be dominated by the influence of physical temperature. Variations in soil and/or litter moisture...

  14. Male Enchenopa treehoppers (Hemiptera: Membracidae) vary mate-searching behavior but not signaling behavior in response to spider silk

    Science.gov (United States)

    Fowler-Finn, Kasey D.; Al-Wathiqui, Nooria; Cruz, Daniel; Al-Wathiqui, Mishal; Rodríguez, Rafael L.

    2014-03-01

    Finding and attracting mates can impose costs on males in terms of increased encounters with, and attraction of, predators. To decrease the likelihood of predation, males may modify mate-acquisition efforts in two main ways: they may reduce mate-searching efforts or they may reduce mate-attraction efforts. The specific behavior that males change in the presence of predator cues should depend upon the nature of risk imposed by the type of predator present in the environment. For example, sit-and-wait predators impose greater costs to males moving in search of mates. Here, we test whether cues of the presence of a sit-and-wait predator lead to a reduction in mate-searching but not mate-acquisition behavior. We used a member of the Enchenopa binotata complex of treehoppers—a clade of vibrationally communicating insects in which males fly in search of mates and produce mate-attraction signals when they land on plant stems. We tested for changes in mate-searching and signaling behaviors when silk from a web-building spider was present or absent. We found that males delayed flight when spider silk was present but only if they were actively searching for mates. These results suggest that males have been selected to reduce predation risk by adjusting how they move about their environment according to the cues of sit-and-wait predators.

  15. Existence of Millisecond-order Stable States in Time-Varying Phase Synchronization Measure in EEG Signals

    CERN Document Server

    Jamal, Wasifa; Maharatna, Koushik

    2016-01-01

    In this paper, we have developed a new measure of understanding the temporal evolution of phase synchronization for EEG signals using cross-electrode information. From this measure it is found that there exists a small number of well-defined phase-synchronized states, each of which is stable for few milliseconds during the execution of a face perception task. We termed these quasi-stable states as synchrostates. We used k-means clustering algorithms to estimate the optimal number of synchrostates from 100 trials of EEG signals over 128 channels. Our results show that these synchrostates exist consistently in all the different trials. It is also found that from the onset of the stimulus, switching between these synchrostates results in well-behaved temporal sequence with repeatability which may be indicative of the dynamics of the cognitive process underlying that task. Therefore these synchrostates and their temporal switching sequences may be used as a new measure of the stability of phase synchrony and info...

  16. Directed differentiation of patient-specific induced pluripotent stem cells identifies the transcriptional repression and epigenetic modification of NKX2-5, HAND1, and NOTCH1 in hypoplastic left heart syndrome.

    Directory of Open Access Journals (Sweden)

    Junko Kobayashi

    Full Text Available The genetic basis of hypoplastic left heart syndrome (HLHS remains unknown, and the lack of animal models to reconstitute the cardiac maldevelopment has hampered the study of this disease. This study investigated the altered control of transcriptional and epigenetic programs that may affect the development of HLHS by using disease-specific induced pluripotent stem (iPS cells. Cardiac progenitor cells (CPCs were isolated from patients with congenital heart diseases to generate patient-specific iPS cells. Comparative gene expression analysis of HLHS- and biventricle (BV heart-derived iPS cells was performed to dissect the complex genetic circuits that may promote the disease phenotype. Both HLHS- and BV heart-derived CPCs were reprogrammed to generate disease-specific iPS cells, which showed characteristic human embryonic stem cell signatures, expressed pluripotency markers, and could give rise to cardiomyocytes. However, HLHS-iPS cells exhibited lower cardiomyogenic differentiation potential than BV-iPS cells. Quantitative gene expression analysis demonstrated that HLHS-derived iPS cells showed transcriptional repression of NKX2-5, reduced levels of TBX2 and NOTCH/HEY signaling, and inhibited HAND1/2 transcripts compared with control cells. Although both HLHS-derived CPCs and iPS cells showed reduced SRE and TNNT2 transcriptional activation compared with BV-derived cells, co-transfection of NKX2-5, HAND1, and NOTCH1 into HLHS-derived cells resulted in synergistic restoration of these promoters activation. Notably, gain- and loss-of-function studies revealed that NKX2-5 had a predominant impact on NPPA transcriptional activation. Moreover, differentiated HLHS-derived iPS cells showed reduced H3K4 dimethylation as well as histone H3 acetylation but increased H3K27 trimethylation to inhibit transcriptional activation on the NKX2-5 promoter. These findings suggest that patient-specific iPS cells may provide molecular insights into complex

  17. A chemically sulfated polysaccharide from Grifola frondos induces HepG2 cell apoptosis by notch1-NF-κB pathway.

    Science.gov (United States)

    Wang, Chun-ling; Meng, Meng; Liu, Sheng-bin; Wang, Li-rui; Hou, Li-hua; Cao, Xiao-hong

    2013-06-05

    Sulfated polysaccharides have been known to inhibit proliferation in tumor cells. However, the molecular mechanisms involved in sulfated polysaccharides-induced apoptosis are still uncharacterized. In this study, the effect of a chemically sulfated polysaccharide obtained from Grifola frondosa (S-GFB) on HepG2 cell proliferation and apoptosis-related mechanism were investigated. It was found that S-GFB inhibited proliferation of HepG2 cells in a dose-dependent manner with IC50 at 48 h of 61 μg ml(-1). The results of scanning electron micrographs indicated that S-GFB induced typical apoptotic morphological feature in HepG2 cells. Flow cytometric analysis demonstrated that S-GFB caused apoptosis of HepG2 cells through cells arrested at S phase. Western-blotting results showed that S-GFB inhibited notch1 expression, IκB-α degradation and NF-κB/p65 translocation from cytoplasm into nucleus. Simultaneously, the apoptotic mechanism of HepG2 cells induced by S-GFB was associated with down regulation of FLIP, and activation of caspase-3 and caspase-8. Taken together, these findings suggest that the S-GFB induces apoptosis through a notch1/NF-κB/p65-mediated caspase pathway. Crown Copyright © 2013. Published by Elsevier Ltd. All rights reserved.

  18. Noise Reduction, Atmospheric Pressure Admittance Estimation and Long-Period Component Extraction in Time-Varying Gravity Signals Using Ensemble Empirical Mode Decomposition

    Directory of Open Access Journals (Sweden)

    Linsong Wang

    2015-01-01

    Full Text Available Time-varying gravity signals, with their nonlinear, non-stationary and multi-scale characteristics, record the physical responses of various geodynamic processes and consist of a blend of signals with various periods and amplitudes, corresponding to numerous phenomena. Superconducting gravimeter (SG records are processed in this study using a multi-scale analytical method and corrected for known effects to reduce noise, to study geodynamic phenomena using their gravimetric signatures. Continuous SG (GWR-C032 gravity and barometric data are decomposed into a series of intrinsic mode functions (IMFs using the ensemble empirical mode decomposition (EEMD method, which is proposed to alleviate some unresolved issues (the mode mixing problem and the end effect of the empirical mode decomposition (EMD. Further analysis of the variously scaled signals is based on a dyadic filter bank of the IMFs. The results indicate that removing the high-frequency IMFs can reduce the natural and man-made noise in the data, which are caused by electronic device noise, Earth background noise and the residual effects of pre-processing. The atmospheric admittances based on frequency changes are estimated from the gravity and the atmospheric pressure IMFs in various frequency bands. These time- and frequency-dependent admittance values can be used effectively to improve the atmospheric correction. Using the EEMD method as a filter, the long-period IMFs are extracted from the SG time-varying gravity signals spanning 7 years. The resulting gravity residuals are well correlated with the gravity effect caused by the _ polar motion after correcting for atmospheric effects.

  19. Exploration of the inhibiting effect of Notch-1 blocker on tumor growth in osteosarcoma mouse models as well as related molecular mechanisms

    Directory of Open Access Journals (Sweden)

    Bin Zhou

    2016-06-01

    Full Text Available Objective: To explore the inhibiting effect of Notch-1 blocker on tumor growth in osteosarcoma mouse models as well as related molecular mechanisms. Methods: SCID mice were selected as experimental subjects, and osteosarcoma mouse models were built through subcutaneous injection of osteosarcoma cells and divided into GSI group and PBS group who received GSI and PBS intervention respectively. 0 d, 5 d, 10 d, 15 d and 20 d after intervention, tumor tissue volume was detected; 20 d after intervention, the contents of pro-apoptosis, proproliferation and invasion-related molecules in tumor tissue were detected. Results: On the 0 d of intervention, tumor volume of GSI group was not significantly different from that of PBS group; 5 d, 10 d, 15 d and 20 d after intervention, tumor volume of GSI group was significantly lower than that of PBS group; 20 d after intervention, the contents of pro-proliferation molecules AEG-1, Orai1, STIM1, PAK5, RIPK4 and β-catenin as well as invasion-promoting molecules Gab2, DLK1, Scr and B7-H3 in tumor tissue of GSI group were significantly lower than those of PBS group, and the contents of pro-apoptosis molecules RanBP9, PD-1, PDL1 and PD-L2 as well as invasion-inhibiting molecules TIMP1 and TIMP2 were significantly higher than those of PBS group. Conclusion: Notch-1 blocker can inhibit tumor growth in osteosarcoma mouse models, and the molecular mechanisms involved in the process include reducing the generation of pro-proliferation molecules and invasion-promoting molecules and increasing the generation of pro-apoptosis and invasion-inhibiting molecules.

  20. Arsenite suppression of BMP signaling in human keratinocytes

    Energy Technology Data Exchange (ETDEWEB)

    Phillips, Marjorie A.; Qin, Qin [Department of Environmental Toxicology, University of California, Davis, CA 95616-8588 (United States); Hu, Qin; Zhao, Bin [State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085 (China); Rice, Robert H., E-mail: rhrice@ucdavis.edu [Department of Environmental Toxicology, University of California, Davis, CA 95616-8588 (United States)

    2013-06-15

    Arsenic, a human skin carcinogen, suppresses differentiation of cultured keratinocytes. Exploring the mechanism of this suppression revealed that BMP-6 greatly increased levels of mRNA for keratins 1 and 10, two of the earliest differentiation markers expressed, a process prevented by co-treatment with arsenite. BMP also stimulated, and arsenite suppressed, mRNA for FOXN1, an important transcription factor driving early keratinocyte differentiation. Keratin mRNAs increased slowly after BMP-6 addition, suggesting they are indirect transcriptional targets. Inhibition of Notch1 activation blocked BMP induction of keratins 1 and 10, while FOXN1 induction was largely unaffected. Supporting a requirement for Notch1 signaling in keratin induction, BMP increased levels of activated Notch1, which was blocked by arsenite. BMP also greatly decreased active ERK, while co-treatment with arsenite maintained active ERK. Inhibition of ERK signaling mimicked BMP by inducing keratin and FOXN1 mRNAs and by increasing active Notch1, effects blocked by arsenite. Of 6 dual-specificity phosphatases (DUSPs) targeting ERK, two were induced by BMP unless prevented by simultaneous exposure to arsenite and EGF. Knockdown of DUSP2 or DUSP14 using shRNAs greatly reduced FOXN1 and keratins 1 and 10 mRNA levels and their induction by BMP. Knockdown also decreased activated Notch1, keratin 1 and keratin 10 protein levels, both in the presence and absence of BMP. Thus, one of the earliest effects of BMP is induction of DUSPs, which increases FOXN1 transcription factor and activates Notch1, both required for keratin gene expression. Arsenite prevents this cascade by maintaining ERK signaling, at least in part by suppressing DUSP expression. - Highlights: • BMP induces FOXN1 transcription. • BMP induces DUSP2 and DUSP14, suppressing ERK activation. • Arsenite suppresses levels of phosphorylated Smad1/5 and FOXN1 and DUSP mRNA. • These actions rationalize arsenite suppression of keratinocyte

  1. Systematic identification of signaling pathways with potential to confer anticancer drug resistance.

    Science.gov (United States)

    Martz, Colin A; Ottina, Kathleen A; Singleton, Katherine R; Jasper, Jeff S; Wardell, Suzanne E; Peraza-Penton, Ashley; Anderson, Grace R; Winter, Peter S; Wang, Tim; Alley, Holly M; Kwong, Lawrence N; Cooper, Zachary A; Tetzlaff, Michael; Chen, Pei-Ling; Rathmell, Jeffrey C; Flaherty, Keith T; Wargo, Jennifer A; McDonnell, Donald P; Sabatini, David M; Wood, Kris C

    2014-12-23

    Cancer cells can activate diverse signaling pathways to evade the cytotoxic action of drugs. We created and screened a library of barcoded pathway-activating mutant complementary DNAs to identify those that enhanced the survival of cancer cells in the presence of 13 clinically relevant, targeted therapies. We found that activation of the RAS-MAPK (mitogen-activated protein kinase), Notch1, PI3K (phosphoinositide 3-kinase)-mTOR (mechanistic target of rapamycin), and ER (estrogen receptor) signaling pathways often conferred resistance to this selection of drugs. Activation of the Notch1 pathway promoted acquired resistance to tamoxifen (an ER-targeted therapy) in serially passaged breast cancer xenografts in mice, and treating mice with a γ-secretase inhibitor to inhibit Notch signaling restored tamoxifen sensitivity. Markers of Notch1 activity in tumor tissue correlated with resistance to tamoxifen in breast cancer patients. Similarly, activation of Notch1 signaling promoted acquired resistance to MAPK inhibitors in BRAF(V600E) melanoma cells in culture, and the abundance of Notch1 pathway markers was increased in tumors from a subset of melanoma patients. Thus, Notch1 signaling may be a therapeutic target in some drug-resistant breast cancers and melanomas. Additionally, multiple resistance pathways were activated in melanoma cell lines with intrinsic resistance to MAPK inhibitors, and simultaneous inhibition of these pathways synergistically induced drug sensitivity. These data illustrate the potential for systematic identification of the signaling pathways controlling drug resistance that could inform clinical strategies and drug development for multiple types of cancer. This approach may also be used to advance clinical options in other disease contexts. Copyright © 2014, American Association for the Advancement of Science.

  2. Osthole prevents cerebral ischemia-reperfusion injury via the Notch signaling pathway.

    Science.gov (United States)

    Guan, Junhong; Wei, Xiangtai; Qu, Shengtao; Lv, Tao; Fu, Qiang; Yuan, Ye

    2017-08-01

    Stroke is a common cerebrovascular disease in aging populations, and constitutes the second highest principle cause of mortality and the principle cause of permanent disability, and ischemic stroke is the primary form. Osthole is a coumarin derivative extracted from the fruits of Cnidium monnieri (L.) Cusson. In this study, we established a rat model of middle cerebral artery occlusion/reperfusion (MCAO/R) in vivo and found that MCAO/R caused cerebral infarction, hippocampus neuronal injury and apoptosis, and also activated the Notch 1 signaling pathway. However, treatment with osthole further enhanced the activity of Notch 1 signaling and reduced the cerebral infarction as well as the hippocampus neuronal injury and apoptosis induced by MCAO/R in a dose-dependent manner. The same results were observed in a primary neuronal oxygen glucose deficiency/reperfusion (OGD/R) model in vitro, and the effect of osthole could be blocked by an inhibitor of Notch 1 signaling, N-[N-(3,5-difluorophenacetyl)-l-alanyl]-S-phenylglycine tert-butyl ester (DAPT). Therefore, we demonstrated that osthole injection prevented rat ischemia-reperfusion injury via activating the Notch 1 signaling pathway in vivo and in vitro in a dose-dependent manner, which may be significant for clinical treatment of ischemic stroke.

  3. SEL-10 is an inhibitor of notch signaling that targets notch for ubiquitin-mediated protein degradation.

    Science.gov (United States)

    Wu, G; Lyapina, S; Das, I; Li, J; Gurney, M; Pauley, A; Chui, I; Deshaies, R J; Kitajewski, J

    2001-11-01

    Notch receptors and their ligands play important roles in both normal animal development and pathogenesis. We show here that the F-box/WD40 repeat protein SEL-10 negatively regulates Notch receptor activity by targeting the intracellular domain of Notch receptors for ubiquitin-mediated protein degradation. Blocking of endogenous SEL-10 activity was done by expression of a dominant-negative form containing only the WD40 repeats. In the case of Notch1, this block leads to an increase in Notch signaling stimulated by either an activated form of the Notch1 receptor or Jagged1-induced signaling through Notch1. Expression of dominant-negative SEL-10 leads to stabilization of the intracellular domain of Notch1. The Notch4 intracellular domain bound to SEL-10, but its activity was not increased as a result of dominant-negative SEL-10 expression. SEL-10 bound Notch4 via the WD40 repeats and bound preferentially to a phosphorylated form of Notch4 in cells. We mapped the region of Notch4 essential for SEL-10 binding to the C-terminal region downstream of the ankyrin repeats. When this C-terminal fragment of Notch4 was expressed in cells, it was highly labile but could be stabilized by the expression of dominant-negative SEL-10. Ubiquitination of Notch1 and Notch4 intracellular domains in vitro was dependent on SEL-10. Although SEL-10 interacts with the intracellular domains of both Notch1 and Notch4, these proteins respond differently to interference with SEL-10 function. Thus, SEL-10 functions to promote the ubiquitination of Notch proteins; however, the fates of these proteins may differ.

  4. Effectiveness of a loudness model for time-varying sounds in equating the loudness of sentences subjected to different forms of signal processing.

    OpenAIRE

    Zorilă, Tudor-Cătălin; Stylianou, Yannis; Flanagan, Sheila; Moore, Brian Cecil

    2017-01-01

    A model for the loudness of time-varying sounds [Glasberg and Moore (2012). J. Audio. Eng. Soc. 50, 331-342] was assessed for its ability to predict the loudness of sentences that were processed to either decrease or increase their dynamic fluctuations. In a paired-comparison task, subjects compared the loudness of unprocessed and processed sentences that had been equalized in (1) root-mean square (RMS) level; (2) the peak long-term loudness predicted by the model; (3) the mean long-term loud...

  5. Exposure to a specific time-varying electromagnetic field inhibits cell proliferation via cAMP and ERK signaling in cancer cells.

    Science.gov (United States)

    Buckner, Carly A; Buckner, Alison L; Koren, Stan A; Persinger, Michael A; Lafrenie, Robert M

    2017-11-10

    Exposure to specific electromagnetic field (EMF) patterns can affect a variety of biological systems. We have shown that exposure to Thomas-EMF, a low-intensity, frequency-modulated (25-6 Hz) EMF pattern, inhibited growth and altered cell signaling in malignant cells. Exposure to Thomas-EMF for 1 h/day inhibited the growth of malignant cells including B16-BL6 mouse melanoma cells, MDA-MB-231, MDA-MB-468, BT-20, and MCF-7 human breast cancer and HeLa cervical cancer cells but did not affect non-malignant cells. The Thomas-EMF-dependent changes in cell proliferation were mediated by adenosine 3',5'-cyclic monophosphate (cAMP) and extracellular-signal-regulated kinase (ERK) signaling pathways. Exposure of malignant cells to Thomas-EMF transiently changed the level of cellular cAMP and promoted ERK phosphorylation. Pharmacologic inhibitors (SQ22536) and activators (forskolin) of cAMP production both blocked the ability of Thomas-EMF to inhibit cell proliferation, and an inhibitor of the MAP kinase pathway (PD98059) was able to partially block Thomas-EMF-dependent inhibition of cell proliferation. Genetic modulation of protein kinase A (PKA) in B16-BL6 cells also altered the effect of Thomas-EMF on cell proliferation. Cells transfected with the constitutively active form of PKA (PKA-CA), which interfered with ERK phosphorylation, also interfered with the Thomas-EMF effect on cell proliferation. The non-malignant cells did not show any EMF-dependent changes in cAMP levels, ERK phosphorylation, or cell growth. These data indicate that exposure to the specific Thomas-EMF pattern can inhibit the growth of malignant cells in a manner dependent on contributions from the cAMP and MAP kinase pathways. Bioelectromagnetics. 2017;9999:XX-XX. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

  6. Inference of targeted interactions of networks with data of driving and driven nodes only by applying fast-varying noise signals

    Science.gov (United States)

    Zhang, Chaoyang; Chen, Yang; Hu, Gang

    2017-08-01

    Most complex social, biological and technological systems can be described by dynamic networks. Reconstructing network structures from measurable data is a fundamental problem in almost all interdisciplinary fields. Network nodes interact to each other, therefore, the accurate reconstruction of any interaction to a node requires data measurements of all its neighboring nodes. When networks are large, these data are often unavailable and thus network inference turns to be difficult. Here, we propose a method to use fast-varying noise driving (FVND) to enhance targeted interactions. With applications of noise driving we can infer any interaction from a driving node to a driven node with known data of these two nodes only while all other nodes are hidden, though the driven node may be actually driven by a large number of hidden nodes. Analytical derivation of the FVND method is conducted and numerical simulations perfectly justify the theoretical derivation.

  7. c-Jun N-terminal kinase 2 prevents luminal cell commitment in normal mammary glands and tumors by inhibiting p53/Notch1 and breast cancer gene 1 expression

    Science.gov (United States)

    Pfefferle, Adam D.; Perou, Charles M.; Van Den Berg, Carla Lynn

    2015-01-01

    Breast cancer is a heterogeneous disease with several subtypes carrying unique prognoses. Patients with differentiated luminal tumors experience better outcomes, while effective treatments are unavailable for poorly differentiated tumors, including the basal-like subtype. Mechanisms governing mammary tumor subtype generation could prove critical to developing better treatments. C-Jun N-terminal kinase 2 (JNK2) is important in mammary tumorigenesis and tumor progression. Using a variety of mouse models, human breast cancer cell lines and tumor expression data, studies herein support that JNK2 inhibits cell differentiation in normal and cancer-derived mammary cells. JNK2 prevents precocious pubertal mammary development and inhibits Notch-dependent expansion of luminal cell populations. Likewise, JNK2 suppresses luminal populations in a p53-competent Polyoma Middle T-antigen tumor model where jnk2 knockout causes p53-dependent upregulation of Notch1 transcription. In a p53 knockout model, JNK2 restricts luminal populations independently of Notch1, by suppressing Brca1 expression and promoting epithelial to mesenchymal transition. JNK2 also inhibits estrogen receptor (ER) expression and confers resistance to fulvestrant, an ER inhibitor, while stimulating tumor progression. These data suggest that therapies inhibiting JNK2 in breast cancer may promote tumor differentiation, improve endocrine therapy response, and inhibit metastasis. PMID:25970777

  8. Inhibition of Delta-induced Notch signaling using fucose analogs.

    Science.gov (United States)

    Schneider, Michael; Kumar, Vivek; Nordstrøm, Lars Ulrik; Feng, Lei; Takeuchi, Hideyuki; Hao, Huilin; Luca, Vincent C; Garcia, K Christopher; Stanley, Pamela; Wu, Peng; Haltiwanger, Robert S

    2018-01-01

    Notch is a cell-surface receptor that controls cell-fate decisions and is regulated by O-glycans attached to epidermal growth factor-like (EGF) repeats in its extracellular domain. Protein O-fucosyltransferase 1 (Pofut1) modifies EGF repeats with O-fucose and is essential for Notch signaling. Constitutive activation of Notch signaling has been associated with a variety of human malignancies. Therefore, tools that inhibit Notch activity are being developed as cancer therapeutics. To this end, we screened L-fucose analogs for their effects on Notch signaling. Two analogs, 6-alkynyl and 6-alkenyl fucose, were substrates of Pofut1 and were incorporated directly into Notch EGF repeats in cells. Both analogs were potent inhibitors of binding to and activation of Notch1 by Notch ligands Dll1 and Dll4, but not by Jag1. Mutagenesis and modeling studies suggest that incorporation of the analogs into EGF8 of Notch1 markedly reduces the ability of Delta ligands to bind and activate Notch1.

  9. SIRT1 regulates endothelial Notch signaling in lung cancer.

    Directory of Open Access Journals (Sweden)

    Mian Xie

    Full Text Available BACKGROUND: Sirtuin 1 (SIRT1 acts as a key regulator of vascular endothelial homeostasis, angiogenesis, and endothelial dysfunction. However, the underlying mechanism for SIRT1-mediated lung carcinoma angiogenesis remains unknown. Herein, we report that the nicotinamide adenine dinucleotide 1 (NAD1-dependent deacetylase SIRT1 can function as an intrinsic negative modulator of Delta-like ligand 4 (DLL4/Notch signaling in Lewis lung carcinoma (LLC xenograft-derived vascular endothelial cells (lung cancer-derived ECs. PRINCIPAL FINDINGS: SIRT1 negatively regulates Notch1 intracellular domain (N1IC and Notch1 target genes HEY1 and HEY2 in response to Delta-like ligand 4 (DLL4 stimulation. Furthermore, SIRT1 deacetylated and repressed N1IC expression. Quantitative chromatin immunoprecipitation (qChIP analysis and gene reporter assay demonstrated that SIRT1 bound to one highly conserved region, which was located at approximately -500 bp upstream of the transcriptional start site of Notch1,and repressed Notch1 transcription. Inhibition of endothelial cell growth and sprouting angiogenesis by DLL4/Notch signaling was enhanced in SIRT1-silenced lung cancer-derived EC and rescued by Notch inhibitor DAPT. In vivo, an increase in proangiogenic activity was observed in Matrigel plugs from endothelial-specific SIRT1 knock-in mice. SIRT1 also enhanced tumor neovascularization and tumor growth of LLC xenografts. CONCLUSIONS: Our results show that SIRT1 facilitates endothelial cell branching and proliferation to increase vessel density and promote lung tumor growth through down-regulation of DLL4/Notch signaling and deacetylation of N1IC. Thus, targeting SIRT1 activity or/and gene expression may represent a novel mechanism in the treatment of lung cancer.

  10. Structure of human POFUT1, its requirement in ligand-independent oncogenic Notch signaling, and functional effects of Dowling-Degos mutations

    Energy Technology Data Exchange (ETDEWEB)

    McMillan, Brian J.; Zimmerman, Brandon; Egan, Emily D.; Lofgren, Michael; Xu, Xiang; Hesser, Anthony; Blacklow, Stephen C.

    2017-03-17

    Protein O-fucosyltransferase-1 (POFUT1), which transfers fucose residues to acceptor sites on serine and threonine residues of epidermal growth factor-like repeats of recipient proteins, is essential for Notch signal transduction in mammals. Here, we examine the consequences of POFUT1 loss on the oncogenic signaling associated with certain leukemia-associated mutations of human Notch1, report the structures of human POFUT1 in free and GDP-fucose bound states, and assess the effects of Dowling-Degos mutations on human POFUT1 function. CRISPR-mediated knockout of POFUT1 in U2OS cells suppresses both normal Notch1 signaling, and the ligand-independent signaling associated with leukemogenic mutations of Notch1. Normal and oncogenic signaling are rescued by wild-type POFUT1 but rescue is impaired by an active-site R240A mutation. The overall structure of the human enzyme closely resembles that of the Caenorhabditis elegans protein, with an overall backbone RMSD of 0.93 Å, despite primary sequence identity of only 39% in the mature protein. GDP-fucose binding to the human enzyme induces limited backbone conformational movement, though the side chains of R43 and D244 reorient to make direct contact with the fucose moiety in the complex. The reported Dowling-Degos mutations of POFUT1, except for M262T, fail to rescue Notch1 signaling efficiently in the CRISPR-engineered POFUT1-/- background. Together, these studies identify POFUT1 as a potential target for cancers driven by Notch1 mutations and provide a structural roadmap for its inhibition.

  11. Retraction: "Down-regulation of Notch-1 is associated with Akt and FoxM1 in inducing cell growth inhibition and apoptosis in prostate cancer cells" by Wang et al.

    Science.gov (United States)

    2016-08-01

    The above article, published online on July 23, 2010 in Wiley Online Library (wileyonlinelibrary.com), has been retracted by agreement between the journal Editor in Chief, Gary S. Stein, and Wiley Periodicals, Inc. The retraction has been agreed following an investigation from Wayne State University involving the first author and the corresponding author that found Figures 1B and 3A to be inappropriately manipulated. REFERENCE Wang Z, Li Y, Ahmad A, Banerjee S, Azmi AS, Kong D, Wojewoda C, Miele L, Sarkar FH. 2011. Down-regulation of Notch-1 is associated with Akt and FoxM1 in inducing cell growth inhibition and apoptosis in prostate cancer cells. J Cell Biochem 112:78-88; doi: 10.1002/jcb.22770. © 2016 Wiley Periodicals, Inc.

  12. State Estimation of the Time-Varying and Spatially Localized Concentration of Signal Molecules from the Stochastic Adsorption Dynamics on the Carbon Nanotube-Based Sensors and Its Application to Tumor Cell Detection.

    Science.gov (United States)

    Jang, Hong; Lee, Jay H; Braatz, Richard D

    2015-01-01

    This paper addresses a problem of estimating time-varying, local concentrations of signal molecules with a carbon-nanotube (CNT)-based sensor array system, which sends signals triggered by monomolecular adsorption/desorption events of proximate molecules on the surfaces of the sensors. Such sensors work on nano-scale phenomena and show inherently stochastic non-Gaussian behavior, which is best represented by the chemical master equation (CME) describing the time evolution of the probabilities for all the possible number of adsorbed molecules. In the CME, the adsorption rate on each sensor is linearly proportional to the local concentration in the bulk phase. State estimators are proposed for these types of sensors that fully address their stochastic nature. For CNT-based sensors motivated by tumor cell detection, the particle filter, which is nonparametric and can handle non-Gaussian distributions, is compared to a Kalman filter that approximates the underlying distributions by Gaussians. In addition, the second-order generalized pseudo Bayesian estimation (GPB2) algorithm and the Markov chain Monte Carlo (MCMC) algorithm are incorporated into KF and PF respectively, for detecting latent drift in the concentration affected by different states of a cell.

  13. State Estimation of the Time-Varying and Spatially Localized Concentration of Signal Molecules from the Stochastic Adsorption Dynamics on the Carbon Nanotube-Based Sensors and Its Application to Tumor Cell Detection.

    Directory of Open Access Journals (Sweden)

    Hong Jang

    Full Text Available This paper addresses a problem of estimating time-varying, local concentrations of signal molecules with a carbon-nanotube (CNT-based sensor array system, which sends signals triggered by monomolecular adsorption/desorption events of proximate molecules on the surfaces of the sensors. Such sensors work on nano-scale phenomena and show inherently stochastic non-Gaussian behavior, which is best represented by the chemical master equation (CME describing the time evolution of the probabilities for all the possible number of adsorbed molecules. In the CME, the adsorption rate on each sensor is linearly proportional to the local concentration in the bulk phase. State estimators are proposed for these types of sensors that fully address their stochastic nature. For CNT-based sensors motivated by tumor cell detection, the particle filter, which is nonparametric and can handle non-Gaussian distributions, is compared to a Kalman filter that approximates the underlying distributions by Gaussians. In addition, the second-order generalized pseudo Bayesian estimation (GPB2 algorithm and the Markov chain Monte Carlo (MCMC algorithm are incorporated into KF and PF respectively, for detecting latent drift in the concentration affected by different states of a cell.

  14. Comparative Analysis of Signal Intensity and Apparent Diffusion Coefficient at Varying b-values in the Brain : Diffusion Weighted-Echo Planar Image (T{sub 2} and FLAIR) Sequence

    Energy Technology Data Exchange (ETDEWEB)

    Oh, Jong Kap [Dept. of Radiology, Cheomdan Medical Center, Gwangju (Korea, Republic of); Im, Jung Yeol [Dept. of Digital Management Information Graduate School of Nambu Univesity, Gwangju (Korea, Republic of)

    2009-09-15

    Diffusion-weighted imaging (DWI) has been demonstrated to be a practical method for the diagnosis of various brain diseases such as acute infarction, brain tumor, and white matter disease. In this study, we used two techniques to examine the average signal intensity (SI) and apparent diffusion coefficient (ADC) of the brains of patients who ranged in age from 10 to 60 years. Our results indicated that the average SI was the highest in amygdala (as derived from DWI), whereas that in the cerebrospinal fluid was the lowest. The average ADC was the highest in the cerebrospinal fluid, whereas the lowest measurement was derived from the pons. The average SI and ADC were higher in T{sub 2}-DW-EPI than in FLAIR-DW-EPI. The higher the b-value, the smaller the average difference in both imaging techniques; the lower the b-value, the greater the average difference. Also, comparative analysis of the brains of patients who had experienced cerebral infarction showed no distinct lesion in the general MR image over time. However, there was a high SI in apparent weighted images. Analysis of other brain diseases (e.g., bleeding, acute, subacute, chronic infarction) indicated SI variance in accordance with characteristics of the two techniques. The higher the SI, the lower the ADC. Taken together, the value of SI and ADC in accordance with frequently occurring areas and various brain disease varies based on the b-value and imaging technique. Because they provide additional useful information in the diagnosis and treatment of patients with various brain diseases through signal recognition, the proper imaging technique and b-value are important for the detection and interpretation of subacute stroke and other brain diseases.

  15. Aberrant activation of notch signaling in human breast cancer.

    Science.gov (United States)

    Stylianou, Spyros; Clarke, Rob B; Brennan, Keith

    2006-02-01

    A role for Notch signaling in human breast cancer has been suggested by both the development of adenocarcinomas in the murine mammary gland following pathway activation and the loss of Numb expression, a negative regulator of the Notch pathway, in a large proportion of breast carcinomas. However, it is not clear currently whether Notch signaling is frequently activated in breast tumors, and how it causes cellular transformation. Here, we show accumulation of the intracellular domain of Notch1 and hence increased Notch signaling in a wide variety of human breast carcinomas. In addition, we show that increased RBP-Jkappa-dependent Notch signaling is sufficient to transform normal breast epithelial cells and that the mechanism of transformation is most likely through the suppression of apoptosis. More significantly, we show that attenuation of Notch signaling reverts the transformed phenotype of human breast cancer cell lines, suggesting that inhibition of Notch signaling may be a therapeutic strategy for this disease.

  16. Toward a NOTCH1/FBXW7/RAS/PTEN-based oncogenetic risk classification of adult T-cell acute lymphoblastic leukemia: a Group for Research in Adult Acute Lymphoblastic Leukemia study.

    Science.gov (United States)

    Trinquand, Amélie; Tanguy-Schmidt, Aline; Ben Abdelali, Raouf; Lambert, Jérôme; Beldjord, Kheira; Lengliné, Etienne; De Gunzburg, Noémie; Payet-Bornet, Dominique; Lhermitte, Ludovic; Mossafa, Hossein; Lhéritier, Véronique; Bond, Jonathan; Huguet, Françoise; Buzyn, Agnès; Leguay, Thibaud; Cahn, Jean-Yves; Thomas, Xavier; Chalandon, Yves; Delannoy, André; Bonmati, Caroline; Maury, Sebastien; Nadel, Bertrand; Macintyre, Elizabeth; Ifrah, Norbert; Dombret, Hervé; Asnafi, Vahid

    2013-12-01

    The Group for Research in Adult Acute Lymphoblastic Leukemia (GRAALL) recently reported a significantly better outcome in T-cell acute lymphoblastic leukemia (T-ALL) harboring NOTCH1 and/or FBXW7 (N/F) mutations compared with unmutated T-ALL. Despite this, one third of patients with N/F-mutated T-ALL experienced relapse. In a series of 212 adult T-ALLs included in the multicenter randomized GRAALL-2003 and -2005 trials, we searched for additional N/K-RAS mutations and PTEN defects (mutations and gene deletion). N/F mutations were identified in 143 (67%) of 212 patients, and lack of N/F mutation was confirmed to be associated with a poor prognosis. K-RAS, N-RAS, and PTEN mutations/deletions were identified in three (1.6%) of 191, 17 (8.9%) of 191, and 21 (12%) of 175 patients, respectively. The favorable prognostic significance of N/F mutations was restricted to patients without RAS/PTEN abnormalities. These observations led us to propose a new T-ALL oncogenetic classifier defining low-risk patients as those with N/F mutation but no RAS/PTEN mutation (97 of 189 patients; 51%) and all other patients (49%; including 13% with N/F and RAS/PTEN mutations) as high-risk patients. In multivariable analysis, this oncogenetic classifier remained the only significant prognostic covariate (event-free survival: hazard ratio [HR], 3.2; 95% CI, 1.9 to 5.15; P < .001; and overall survival: HR, 3.2; 95% CI, 1.9 to 5.6; P < .001). These data demonstrate that the presence of N/F mutations in the absence of RAS or PTEN abnormalities predicts good outcome in almost 50% of adult T-ALL. Conversely, the absence of N/F or presence of RAS/PTEN alterations identifies the remaining cohort of patients with poor prognosis.

  17. Notch-Tnf signalling is required for development and homeostasis of arterial valves.

    Science.gov (United States)

    Wang, Yidong; Wu, Bingruo; Farrar, Emily; Lui, Wendy; Lu, Pengfei; Zhang, Donghong; Alfieri, Christina M; Mao, Kai; Chu, Ming; Yang, Di; Xu, Di; Rauchman, Michael; Taylor, Verdon; Conway, Simon J; Yutzey, Katherine E; Butcher, Jonathan T; Zhou, Bin

    2017-03-01

    Congenital anomalies of arterial valves are common birth defects, leading to valvar stenosis. With no pharmaceutical treatment that can prevent the disease progression, prosthetic replacement is the only choice of treatment, incurring considerable morbidity and mortality. Animal models presenting localized anomalies and stenosis of congenital arterial valves similar to that of humans are critically needed research tools to uncover developmental molecular mechanisms underlying this devastating human condition. We generated and characterized mouse models with conditionally altered Notch signalling in endothelial or interstitial cells of developing valves. Mice with inactivation of Notch1 signalling in valvar endothelial cells (VEC) developed congenital anomalies of arterial valves including bicuspid aortic valves and valvar stenosis. Notch1 signalling in VEC was required for repressing proliferation and activating apoptosis of valvar interstitial cells (VIC) after endocardial-to-mesenchymal transformation (EMT). We showed that Notch signalling regulated Tnfα expression in vivo, and Tnf signalling was necessary for apoptosis of VIC and post-EMT development of arterial valves. Furthermore, activation or inhibition of Notch signalling in cultured pig aortic VEC-promoted or suppressed apoptosis of VIC, respectively. We have now met the need of critical animal models and shown that Notch-Tnf signalling balances proliferation and apoptosis for post-EMT development of arterial valves. Our results suggest that mutations in its components may lead to congenital anomaly of aortic valves and valvar stenosis in humans.

  18. Galectin-3 Inhibits Osteoblast Differentiation through Notch Signaling12

    Science.gov (United States)

    Nakajima, Kosei; Kho, Dhong Hyo; Yanagawa, Takashi; Harazono, Yosuke; Gao, Xiaoge; Hogan, Victor; Raz, Avraham

    2014-01-01

    Patients with bone cancer metastasis suffer from unbearable pain and bone fractures due to bone remodeling. This is caused by tumor cells that disturb the bone microenvironment. Here, we have investigated the role of tumor-secreted sugar-binding protein, i.e., galectin-3, on osteoblast differentiation and report that it downregulates the expression of osteoblast differentiation markers, e.g., RUNX2, SP7, ALPL, COL1A1, IBSP, and BGLAP, of treated human fetal osteoblast (hFOB) cells. Co-culturing of hFOB cells with human breast cancer BT-549 and prostate cancer LNCaP cells harboring galectin-3 has resulted in inhibition of osteoblast differentiation by the secreted galectin-3 into culture medium. The inhibitory effect of galectin-3 was found to be through its binding to Notch1 in a sugar-dependent manner that has led to accelerated Notch1 cleavage and activation of Notch signaling. Taken together, our findings show that soluble galectin-3 in the bone microenvironment niche regulates bone remodeling through Notch signaling, suggesting a novel bone metastasis therapeutic target. PMID:25425968

  19. Silybin-mediated inhibition of Notch signaling exerts antitumor activity in human hepatocellular carcinoma cells.

    Directory of Open Access Journals (Sweden)

    Song Zhang

    Full Text Available Hepatocellular carcinoma (HCC is a global health burden that is associated with limited treatment options and poor patient prognoses. Silybin (SIL, an antioxidant derived from the milk thistle plant (Silybum marianum, has been reported to exert hepatoprotective and antitumorigenic effects both in vitro and in vivo. While SIL has been shown to have potent antitumor activity against various types of cancer, including HCC, the molecular mechanisms underlying the effects of SIL remain largely unknown. The Notch signaling pathway plays crucial roles in tumorigenesis and immune development. In the present study, we assessed the antitumor activity of SIL in human HCC HepG2 cells in vitro and in vivo and explored the roles of the Notch pathway and of the apoptosis-related signaling pathway on the activity of SIL. SIL treatment resulted in a dose- and time-dependent inhibition of HCC cell viability. Additionally, SIL exhibited strong antitumor activity, as evidenced not only by reductions in tumor cell adhesion, migration, intracellular glutathione (GSH levels and total antioxidant capability (T-AOC but also by increases in the apoptotic index, caspase3 activity, and reactive oxygen species (ROS. Furthermore, SIL treatment decreased the expression of the Notch1 intracellular domain (NICD, RBP-Jκ, and Hes1 proteins, upregulated the apoptosis pathway-related protein Bax, and downregulated Bcl2, survivin, and cyclin D1. Notch1 siRNA (in vitro or DAPT (a known Notch1 inhibitor, in vivo further enhanced the antitumor activity of SIL, and recombinant Jagged1 protein (a known Notch ligand in vitro attenuated the antitumor activity of SIL. Taken together, these data indicate that SIL is a potent inhibitor of HCC cell growth that targets the Notch signaling pathway and suggest that the inhibition of Notch signaling may be a novel therapeutic intervention for HCC.

  20. Smoothly Varying Bright Blazars

    Science.gov (United States)

    Van Alfen, Nicholas; Hindman, Lauren; Moody, Joseph Ward; Biancardi, Rochelle; Whipple, Parkes; Gaunt, Caleb

    2018-01-01

    It is becoming increasingly apparent that blazar light can vary sinusoidally with periods of hundreds of days to tens of years. Such behavior is expected of, among other things, jets coming from binary black holes. To look for general variability in lesser-known blazars and AGN, in 2015-2016 we monitored 182 objects with Johnson V-band magnitudes reported as being < 16. In all, this campaign generated 22,000 frames from 2,000 unique pointings. We find that approximately one dozen of these objects show evidence of smooth variability consistent with sinusoidal periods. We report on the entire survey sample, highlighting those that show sinusoidal variations.

  1. Tracking time-varying coefficient-functions

    DEFF Research Database (Denmark)

    Nielsen, Henrik Aalborg; Nielsen, Torben Skov; Joensen, Alfred K.

    2000-01-01

    is a combination of recursive least squares with exponential forgetting and local polynomial regression. It is argued, that it is appropriate to let the forgetting factor vary with the value of the external signal which is the argument of the coefficient functions. Some of the key properties of the modified method...... are studied by simulation...

  2. Regulation of Notch signaling during T- and B-cell development by O-fucose glycans.

    Science.gov (United States)

    Stanley, Pamela; Guidos, Cynthia J

    2009-07-01

    Notch signaling is required for the development of all T cells and marginal zone (MZ) B cells. Specific roles in T- and B-cell differentiation have been identified for different Notch receptors, the canonical Delta-like (Dll) and Jagged (Jag) Notch ligands, and downstream effectors of Notch signaling. Notch receptors and ligands are post-translationally modified by the addition of glycans to extracellular domain epidermal growth factor-like (EGF) repeats. The O-fucose glycans of Notch cell-autonomously modulate Notch-ligand interactions and the strength of Notch signaling. These glycans are initiated by protein O-fucosyltransferase 1 (Pofut1), and elongated by the transfer of N-acetylglucosamine (GlcNAc) to the fucose by beta1,3GlcNAc-transferases termed lunatic, manic, or radical fringe. This review discusses T- and B-cell development from progenitors deficient in O-fucose glycans. The combined data show that Lfng and Mfng regulate T-cell development by enhancing the interactions of Notch1 in T-cell progenitors with Dll4 on thymic epithelial cells. In the spleen, Lfng and Mfng cooperate to modify Notch2 in MZ B progenitors, enhancing their interaction with Dll1 on endothelial cells and regulating MZ B-cell production. Removal of O-fucose affects Notch signaling in myelopoiesis and lymphopoiesis, and the O-fucose glycan in the Notch1 ligand-binding domain is required for optimal T-cell development.

  3. Primary cilia maintain corneal epithelial homeostasis by regulation of the Notch signaling pathway.

    Science.gov (United States)

    Grisanti, Laura; Revenkova, Ekaterina; Gordon, Ronald E; Iomini, Carlo

    2016-06-15

    Primary cilia have been linked to signaling pathways involved in cell proliferation, cell motility and cell polarity. Defects in ciliary function result in developmental abnormalities and multiple ciliopathies. Patients affected by severe ciliopathies, such as Meckel syndrome, present several ocular surface disease conditions of unclear pathogenesis. Here, we show that primary cilia are predominantly present on basal cells of the mouse corneal epithelium (CE) throughout development and in the adult. Conditional ablation of cilia in the CE leads to an increase in proliferation and vertical migration of basal corneal epithelial cells (CECs). A consequent increase in cell density of suprabasal layers results in a thicker than normal CE. Surprisingly, in cilia-deficient CE, cilia-mediated signaling pathways, including Hh and Wnt pathways, were not affected but the intensity of Notch signaling was severely diminished. Although Notch1 and Notch2 receptors were expressed normally, nuclear Notch1 intracellular domain (N1ICD) expression was severely reduced. Postnatal development analysis revealed that in cilia-deficient CECs downregulation of the Notch pathway precedes cell proliferation defects. Thus, we have uncovered a function of the primary cilium in maintaining homeostasis of the CE by balancing proliferation and vertical migration of basal CECs through modulation of Notch signaling. © 2016. Published by The Company of Biologists Ltd.

  4. Digital repetitive control under varying frequency conditions

    CERN Document Server

    Ramos, Germán A; Olm, Josep M

    2013-01-01

    The tracking/rejection of periodic signals constitutes a wide field of research in the control theory and applications area. Repetitive Control has proven to be an efficient way to face this topic. However, in some applications the frequency of the reference/disturbance signal is time-varying or uncertain. This causes an important performance degradation in the standard Repetitive Control scheme. This book presents some solutions to apply Repetitive Control in varying frequency conditions without loosing steady-state performance. It also includes a complete theoretical development and experimental results in two representative systems. The presented solutions are organized in two complementary branches: varying sampling period Repetitive Control and High Order Repetitive Control. The first approach allows dealing with large range frequency variations while the second allows dealing with small range frequency variations. The book also presents applications of the described techniques to a Roto-magnet plant and...

  5. varying elastic parameters distributions

    KAUST Repository

    Moussawi, Ali

    2014-12-01

    The experimental identication of mechanical properties is crucial in mechanics for understanding material behavior and for the development of numerical models. Classical identi cation procedures employ standard shaped specimens, assume that the mechanical elds in the object are homogeneous, and recover global properties. Thus, multiple tests are required for full characterization of a heterogeneous object, leading to a time consuming and costly process. The development of non-contact, full- eld measurement techniques from which complex kinematic elds can be recorded has opened the door to a new way of thinking. From the identi cation point of view, suitable methods can be used to process these complex kinematic elds in order to recover multiple spatially varying parameters through one test or a few tests. The requirement is the development of identi cation techniques that can process these complex experimental data. This thesis introduces a novel identi cation technique called the constitutive compatibility method. The key idea is to de ne stresses as compatible with the observed kinematic eld through the chosen class of constitutive equation, making possible the uncoupling of the identi cation of stress from the identi cation of the material parameters. This uncoupling leads to parametrized solutions in cases where 5 the solution is non-unique (due to unknown traction boundary conditions) as demonstrated on 2D numerical examples. First the theory is outlined and the method is demonstrated in 2D applications. Second, the method is implemented within a domain decomposition framework in order to reduce the cost for processing very large problems. Finally, it is extended to 3D numerical examples. Promising results are shown for 2D and 3D problems.

  6. Immunolocalization of notch signaling protein molecules in a maxillary chondrosarcoma and its recurrent tumor

    Directory of Open Access Journals (Sweden)

    Siar CH

    2010-10-01

    Full Text Available Abstract Background Notch receptors are critical determinants of cell fate in a variety of organisms. Notch signaling is involved in the chondrogenic specification of neural crest cells. Aberrant Notch activity has been implicated in numerous human diseases including cancers; however its role in chondrogenic tumors has not been clarified. Method Tissue samples from a case of primary chondrosarcoma of the maxilla and its recurrent tumor were examined immunohistochemically for Notch1-4 and their ligands (Jagged1, Jagged2 and Delta1 expression. Results Both primary and recurrent tumors were histopathologically diagnosed as conventional hyaline chondrosarcoma (WHO Grade I. Hypercellular tumor areas strongly expressed Notch3 and Jagged1 in spindle and pleomorphic cells suggesting up-regulation of these protein molecules at sites of tumor proliferation. Expression patterns were distinct with some overlap. Differentiated malignant and atypical chondrocytes demonstrated variable expression levels of Jagged1, and weak to absent staining for Notch1, 4 and Delta1. Protein immunolocalization was largely membranous and cytoplasmic, sometimes outlining the lacunae of malignant chondrocytes. Hyaline cartilage demonstrated a diffuse or granular precipitation of Jagged1 suggesting presence of soluble Jagged1 activity at sites of abnormal chondrogenesis. No immunoreactivity for the other Notch members was observed. Calcified cartilage was consistently Notch-negative indicating down-regulation of Notch with cartilage maturation. Stromal components namely endothelial cells and fibroblasts variably expressed Notch1, 3 and Jagged1 but were mildly or non-reactive for the other members. Conclusions Results indicate that Notch signaling pathway may participate in cellular differentiation and proliferation in chondrosarcoma. Findings implicate Notch3 and Jagged1 as key molecules that influence the differentiation and maturation of cells of chondrogenic lineage.

  7. Opposing actions of endocannabinoids on cholangiocarcinoma growth is via the differential activation of Notch signaling

    Energy Technology Data Exchange (ETDEWEB)

    Frampton, Gabriel; Coufal, Monique [Department of Internal Medicine, Texas A and M Health Science Center College of Medicine, Temple, TX (United States); Li, Huang [Department of Internal Medicine, Texas A and M Health Science Center College of Medicine, Temple, TX (United States); Department of Hepatobiliary Surgery, First Affiliated Hospital, Sun Yat-Sen University, Guangzhou (China); Ramirez, Jonathan [Digestive Disease Research Center, Scott and White Hospital, Temple, TX (United States); DeMorrow, Sharon, E-mail: demorrow@medicine.tamhsc.edu [Department of Internal Medicine, Texas A and M Health Science Center College of Medicine, Temple, TX (United States); Digestive Disease Research Center, Scott and White Hospital, Temple, TX (United States)

    2010-05-15

    The endocannabinoids anandamide (AEA) and 2-arachidonylglycerol (2-AG) have opposing effects on cholangiocarcinoma growth. Implicated in cancer, Notch signaling requires the {gamma}-secretase complex for activation. The aims of this study were to determine if the opposing effects of endocannabinoids depend on the differential activation of the Notch receptors and to demonstrate that the differential activation of these receptors are due to presenilin 1 containing- and presenilin 2 containing-{gamma}-secretase complexes. Mz-ChA-1 cells were treated with AEA or 2-AG. Notch receptor expression, activation, and nuclear translocation were determined. Specific roles for Notch 1 and 2 on cannabinoid-induced effects were determined by transient transfection of Notch 1 or 2 shRNA vectors before stimulation with AEA or 2-AG. Expression of presenilin 1 and 2 was determined after AEA or 2-AG treatment, and the involvement of presenilin 1 and 2 in the cannabinoid-induced effects was demonstrated in cell lines with low presenilin 1 or 2 expression. Antiproliferative effects of AEA required increased Notch 1 mRNA, activation, and nuclear translocation, whereas the growth-promoting effects induced by 2-AG required increased Notch 2 mRNA expression, activation, and nuclear translocation. AEA increased presenilin 1 expression and recruitment into the {gamma}-secretase complex, whereas 2-AG increased expression and recruitment of presenilin 2. The development of novel therapeutic strategies aimed at modulating the endocannabinoid system or mimicking the mode of action of AEA on Notch signaling pathways would prove beneficial for cholangiocarcinoma management.

  8. hCLP46 regulates U937 cell proliferation via Notch signaling pathway

    Energy Technology Data Exchange (ETDEWEB)

    Ma, Wenzhan; Du, Jie; Chu, Qiaoyun [College of Life Science, Graduate University of Chinese Academy of Sciences, Beijing 100049 (China); Wang, Youxin [School of Public Health and Family Medicine, Capital Medical University, Beijing 100069 (China); Liu, Lixin [College of Life Science, Graduate University of Chinese Academy of Sciences, Beijing 100049 (China); Song, Manshu [School of Public Health and Family Medicine, Capital Medical University, Beijing 100069 (China); Wang, Wei, E-mail: wei6014@yahoo.com [College of Life Science, Graduate University of Chinese Academy of Sciences, Beijing 100049 (China); School of Public Health and Family Medicine, Capital Medical University, Beijing 100069 (China)

    2011-04-29

    Highlights: {yields} Knock down of hCLP46 by RNAi impairs mammalian Notch signaling. {yields} hCLP46 affects neither cell surface Notch1 expression nor ligand-receptor binding. {yields} Knock down of hCLP46 inhibits U937 cell-growth by up-regulation of CDKN1B. -- Abstract: Human CAP10-like protein 46 kDa (hCLP46) is the homolog of Rumi, which is the first identified protein O-glucosyltransferase that modifies Notch receptor in Drosophila. Dysregulation of hCLP46 occurs in many hematologic diseases, but the role of hCLP46 remains unclear. Knockdown of hCLP46 by RNA interference resulted in decreased protein levels of endogenous Notch1, Notch intracellular domain (NICD) and Notch target gene Hes-1, suggesting the impairment of the Notch signaling. However, neither cell surface Notch expression nor ligand binding activities were affected. In addition, down-regulated expression of hCLP46 inhibited the proliferation of U937 cells, which was correlated with increased cyclin-dependent kinase inhibitor (CDKI) CDKN1B (p27) and decreased phosphorylation of retinoblastoma (RB) protein. We showed that lack of hCLP46 results in impaired ligand induced Notch activation in mammalian cell, and hCLP46 regulates the proliferation of U937 cell through CDKI-RB signaling pathway, which may be important for the pathogenesis of leukemia.

  9. Lawsonia intracellularis exploits β-catenin/Wnt and Notch signalling pathways during infection of intestinal crypt to alter cell homeostasis and promote cell proliferation.

    Directory of Open Access Journals (Sweden)

    Yang W Huan

    Full Text Available Lawsonia intracellularis is an obligate intracellular bacterial pathogen that causes proliferative enteropathy (PE in pigs. L. intracellularis infection causes extensive intestinal crypt cell proliferation and inhibits secretory and absorptive cell differentiation. However, the affected host upstream cellular pathways leading to PE are still unknown. β-catenin/Wnt signalling is essential in maintaining intestinal stem cell (ISC proliferation and self-renewal capacity, while Notch signalling governs differentiation of secretory and absorptive lineage specification. Therefore, in this report we used immunofluorescence (IF and quantitative reverse transcriptase PCR (RTqPCR to examine β-catenin/Wnt and Notch-1 signalling levels in uninfected and L. intracellularis infected pig ileums at 3, 7, 14, 21 and 28 days post challenge (dpc. We found that while the significant increase in Ki67+ nuclei in crypts at the peak of L. intracellularis infection suggested enhanced cell proliferation, the expression of c-MYC and ASCL2, promoters of cell growth and ISC proliferation respectively, was down-regulated. Peak infection also coincided with enhanced cytosolic and membrane-associated β-catenin staining and induction of AXIN2 and SOX9 transcripts, both encoding negative regulators of β-catenin/Wnt signalling and suggesting a potential alteration to β-catenin/Wnt signalling levels, with differential regulation of the expression of its target genes. We found that induction of HES1 and OLFM4 and the down-regulation of ATOH1 transcript levels was consistent with the increased Notch-1 signalling in crypts at the peak of infection. Interestingly, the significant down-regulation of ATOH1 transcript levels coincided with the depletion of MUC2 expression at 14 dpc, consistent with the role of ATOH1 in promoting goblet cell maturation. The lack of significant change to LGR5 transcript levels at the peak of infection suggested that the crypt hyperplasia was not due

  10. Lawsonia intracellularis exploits β-catenin/Wnt and Notch signalling pathways during infection of intestinal crypt to alter cell homeostasis and promote cell proliferation.

    Science.gov (United States)

    Huan, Yang W; Bengtsson, Rebecca J; MacIntyre, Neil; Guthrie, Jack; Finlayson, Heather; Smith, Sionagh H; Archibald, Alan L; Ait-Ali, Tahar

    2017-01-01

    Lawsonia intracellularis is an obligate intracellular bacterial pathogen that causes proliferative enteropathy (PE) in pigs. L. intracellularis infection causes extensive intestinal crypt cell proliferation and inhibits secretory and absorptive cell differentiation. However, the affected host upstream cellular pathways leading to PE are still unknown. β-catenin/Wnt signalling is essential in maintaining intestinal stem cell (ISC) proliferation and self-renewal capacity, while Notch signalling governs differentiation of secretory and absorptive lineage specification. Therefore, in this report we used immunofluorescence (IF) and quantitative reverse transcriptase PCR (RTqPCR) to examine β-catenin/Wnt and Notch-1 signalling levels in uninfected and L. intracellularis infected pig ileums at 3, 7, 14, 21 and 28 days post challenge (dpc). We found that while the significant increase in Ki67+ nuclei in crypts at the peak of L. intracellularis infection suggested enhanced cell proliferation, the expression of c-MYC and ASCL2, promoters of cell growth and ISC proliferation respectively, was down-regulated. Peak infection also coincided with enhanced cytosolic and membrane-associated β-catenin staining and induction of AXIN2 and SOX9 transcripts, both encoding negative regulators of β-catenin/Wnt signalling and suggesting a potential alteration to β-catenin/Wnt signalling levels, with differential regulation of the expression of its target genes. We found that induction of HES1 and OLFM4 and the down-regulation of ATOH1 transcript levels was consistent with the increased Notch-1 signalling in crypts at the peak of infection. Interestingly, the significant down-regulation of ATOH1 transcript levels coincided with the depletion of MUC2 expression at 14 dpc, consistent with the role of ATOH1 in promoting goblet cell maturation. The lack of significant change to LGR5 transcript levels at the peak of infection suggested that the crypt hyperplasia was not due to the expansion

  11. Notch signaling change in pulmonary vascular remodeling in rats with pulmonary hypertension and its implication for therapeutic intervention.

    Science.gov (United States)

    Qiao, Lina; Xie, Liang; Shi, Kun; Zhou, Tongfu; Hua, Yimin; Liu, Hanmin

    2012-01-01

    Pulmonary hypertension (PH) is a fatal disease that lacks an effective therapy. Notch signaling pathway plays a crucial role in the angiogenesis and vascular remodeling. However, its roles in vascular remodeling in PH have not been well studied. In the current study, using hypoxia-induced PH model in rat, we examined the expression of Notch and its downstream factors. Then, we used vessel strip culture system and γ-secretase inhibitor DAPT, a Notch signaling inhibitor to determine the effect of Notch signaling in vascular remodeling and its potential therapeutic value. Our results indicated that Notch 1-4 were detected in the lung tissue with variable levels in different cell types such as smooth muscle cells and endothelial cells of pulmonary artery, bronchia, and alveoli. In addition, following the PH induction, all of Notch1, Notch3, Notch4 receptor, and downstream factor, HERP1 in pulmonary arteries, mRNA expressions were increased with a peak at 1-2 weeks. Furthermore, the vessel wall thickness from rats with hypoxia treatment increased after cultured for 8 days, which could be decreased approximately 30% by DAPT, accompanied with significant increase of expression level of apoptotic factors (caspase-3 and Bax) and transformation of vascular smooth muscle cell (VSMC) phenotype from synthetic towards contractile. In conclusion, the current study suggested Notch pathway plays an important role in pulmonary vascular remodeling in PH and targeting Notch signaling pathway could be a valuable approach to design new therapy for PH.

  12. Notch signaling change in pulmonary vascular remodeling in rats with pulmonary hypertension and its implication for therapeutic intervention.

    Directory of Open Access Journals (Sweden)

    Lina Qiao

    Full Text Available Pulmonary hypertension (PH is a fatal disease that lacks an effective therapy. Notch signaling pathway plays a crucial role in the angiogenesis and vascular remodeling. However, its roles in vascular remodeling in PH have not been well studied. In the current study, using hypoxia-induced PH model in rat, we examined the expression of Notch and its downstream factors. Then, we used vessel strip culture system and γ-secretase inhibitor DAPT, a Notch signaling inhibitor to determine the effect of Notch signaling in vascular remodeling and its potential therapeutic value. Our results indicated that Notch 1-4 were detected in the lung tissue with variable levels in different cell types such as smooth muscle cells and endothelial cells of pulmonary artery, bronchia, and alveoli. In addition, following the PH induction, all of Notch1, Notch3, Notch4 receptor, and downstream factor, HERP1 in pulmonary arteries, mRNA expressions were increased with a peak at 1-2 weeks. Furthermore, the vessel wall thickness from rats with hypoxia treatment increased after cultured for 8 days, which could be decreased approximately 30% by DAPT, accompanied with significant increase of expression level of apoptotic factors (caspase-3 and Bax and transformation of vascular smooth muscle cell (VSMC phenotype from synthetic towards contractile. In conclusion, the current study suggested Notch pathway plays an important role in pulmonary vascular remodeling in PH and targeting Notch signaling pathway could be a valuable approach to design new therapy for PH.

  13. Notch2 Signaling Maintains NSC Quiescence in the Murine Ventricular-Subventricular Zone

    Directory of Open Access Journals (Sweden)

    Anna Engler

    2018-01-01

    Full Text Available Neurogenesis continues in the ventricular-subventricular zone (V-SVZ of the adult forebrain from quiescent neural stem cells (NSCs. V-SVZ NSCs are a reservoir for new olfactory bulb (OB neurons that migrate through the rostral migratory stream (RMS. To generate neurons, V-SVZ NSCs need to activate and enter the cell cycle. The mechanisms underlying NSC transition from quiescence to activity are poorly understood. We show that Notch2, but not Notch1, signaling conveys quiescence to V-SVZ NSCs by repressing cell-cycle-related genes and neurogenesis. Loss of Notch2 activates quiescent NSCs, which proliferate and generate new neurons of the OB lineage. Notch2 deficiency results in accelerated V-SVZ NSC exhaustion and an aging-like phenotype. Simultaneous loss of Notch1 and Notch2 resembled the total loss of Rbpj-mediated canonical Notch signaling; thus, Notch2 functions are not compensated in NSCs, and Notch2 is indispensable for the maintenance of NSC quiescence in the adult V-SVZ.

  14. Magnesium Chloride promotes Osteogenesis through Notch signaling activation and expansion of Mesenchymal Stem Cells.

    Science.gov (United States)

    Díaz-Tocados, Juan M; Herencia, Carmen; Martínez-Moreno, Julio M; Montes de Oca, Addy; Rodríguez-Ortiz, Maria E; Vergara, Noemi; Blanco, Alfonso; Steppan, Sonja; Almadén, Yolanda; Rodríguez, Mariano; Muñoz-Castañeda, Juan R

    2017-08-10

    Mesenchymal stem cells (MSC) are osteoblasts progenitors and a variety of studies suggest that they may play an important role for the health in the field of bone regeneration. Magnesium supplementation is gaining importance as adjuvant treatment to improve osteogenesis, although the mechanisms involving this process are not well understood. The objective of this study was to investigate the effects of magnesium on MSC differentiation. Here we show that in rat bone marrow MSC, magnesium chloride increases MSC proliferation in a dose-dependent manner promoting osteogenic differentiation and mineralization. These effects are reduced by 2-APB administration, an inhibitor of magnesium channel TRPM7. Of note, magnesium supplementation did not increase the canonical Wnt/β-catenin pathway, although it promoted the activation of Notch1 signaling, which was also decreased by addition of 2-APB. Electron microscopy showed higher proliferation, organization and maturation of osteoblasts in bone decellularized scaffolds after magnesium addition. In summary, our results demonstrate that magnesium chloride enhances MSC proliferation by Notch1 signaling activation and induces osteogenic differentiation, shedding light on the understanding of the role of magnesium during bone regeneration.

  15. Estimation of Time Varying Autoregressive Symmetric Alpha Stable

    Data.gov (United States)

    National Aeronautics and Space Administration — In this work, we present a novel method for modeling time-varying autoregressive impulsive signals driven by symmetric alpha stable distributions. The proposed...

  16. Neuronal apoptosis and synaptic density in the dentate gyrus of ischemic rats' response to chronic mild stress and the effects of Notch signaling.

    Directory of Open Access Journals (Sweden)

    Shaohua Wang

    Full Text Available Our previous research highlighted an inconsistency with Notch1 signaling-related compensatory neurogenesis after chronic mild stress (CMS in rodents suffering from cerebral ischemia, which continue to display post-stroke depressive symptoms. Here, we hypothesize that CMS aggrandized ischemia-related apoptosis injury and worsened synaptic integrity via gamma secretase-meditated Notch1 signaling. Adult rats were exposed to a CMS paradigm after left middle cerebral artery occlusion (MCAO. Open-field and sucrose consumption testing were employed to assess depression-like behavior. Gene expression of pro-apoptotic Bax, anti-apoptotic Bcl-2, and synaptic density-related synaptophysin were measured by western blotting and real-time PCR on Day 28 after MCAO surgery. CMS induced depressive behaviors in ischemic rats, which was accompanied by an elevation in Bax/bcl-2 ratio, TUNEL staining in neurons and reduced synaptophysin expression in the dentate gyrus. These collective effects were reversed by the gamma-secretase inhibitor DAPT (N-[N-(3,5-difluorophenacetyl-L-alanyl]-S-phenyl-glycine t-butyl ester. We found that post-stroke stressors made neurons in the dentate gyrus vulnerable to apoptosis, which supports a putative role for Notch signaling in neural integrity, potentially in newborn cells' synaptic deficit with regard to preexisting cells. These findings suggest that post-stroke depression therapeutically benefits from blocking gamma secretase mediated Notch signaling, and whether this signaling pathway could be a therapeutic target needs to be further investigated.

  17. Time-frequency representation based on time-varying ...

    Indian Academy of Sciences (India)

    Abstract. A parametric time-frequency representation is presented based on time- varying autoregressive model (TVAR), followed by applications to non-stationary vibration signal processing. The identification of time-varying model coefficients and the determination of model order, are addressed by means of neural ...

  18. Audio Effects Based on Biorthogonal Time-Varying Frequency Warping

    Directory of Open Access Journals (Sweden)

    Sergio Cavaliere

    2001-03-01

    Full Text Available We illustrate the mathematical background and musical use of a class of audio effects based on frequency warping. These effects alter the frequency content of a signal via spectral mapping. They can be implemented in dispersive tapped delay lines based on a chain of all-pass filters. In a homogeneous line with first-order all-pass sections, the signal formed by the output samples at a given time is related to the input via the Laguerre transform. However, most musical signals require a time-varying frequency modification in order to be properly processed. Vibrato in musical instruments or voice intonation in the case of vocal sounds may be modeled as small and slow pitch variations. Simulation of these effects requires techniques for time-varying pitch and/or brightness modification that are very useful for sound processing. The basis for time-varying frequency warping is a time-varying version of the Laguerre transformation. The corresponding implementation structure is obtained as a dispersive tapped delay line, where each of the frequency dependent delay element has its own phase response. Thus, time-varying warping results in a space-varying, inhomogeneous, propagation structure. We show that time-varying frequency warping is associated to an expansion over biorthogonal sets generalizing the discrete Laguerre basis. Slow time-varying characteristics lead to slowly varying parameter sequences. The corresponding sound transformation does not suffer from discontinuities typical of delay lines based on unit delays.

  19. Tracking Time-Varying Coefficient-Functions

    DEFF Research Database (Denmark)

    Nielsen, Henrik Aalborg; Nielsen, Torben Skov; Joensen, Alfred K.

    1999-01-01

    of recursive least squares with exponential forgetting and local polynomial regression. However, it is argued, that it is appropriate to let the forgetting factor vary with the value of the external signal shich is argument of the coeffieient-functions.The properties of the modified method are sutdied...... by simulation. A particular feature is that this effectiv forgetting factor will adapt to the bandwidth used so that the effective number of observtions behind the estimates will be almost independent of the actual bandwidth or of the type of bandwidth selection used (fixed or nearest neighbour). The choice...

  20. Varying Collimation for Dark-Field Extraction

    Directory of Open Access Journals (Sweden)

    Ge Wang

    2009-01-01

    Full Text Available Although x-ray imaging is widely used in biomedical applications, biological soft tissues have small density changes, leading to low contrast resolution for attenuation-based x-ray imaging. Over the past years, x-ray small-angle scattering was studied as a new contrast mechanism to enhance subtle structural variation within the soft tissue. In this paper, we present a detection method to extract this type of x-ray scattering data, which are also referred to as dark-field signals. The key idea is to acquire an x-ray projection multiple times with varying collimation before an x-ray detector array. The projection data acquired with a collimator of a sufficiently high collimation aspect ratio contain mainly the primary beam with little scattering, while the data acquired with an appropriately reduced collimation aspect ratio include both the primary beam and small-angle scattering signals. Then, analysis of these corresponding datasets will produce desirable dark-field signals; for example, via digitally subtraction. In the numerical experiments, the feasibility of our dark-field detection technology is demonstrated in Monte Carlo simulation. The results show that the acquired dark field signals can clearly reveal the structural information of tissues in terms of Rayleigh scattering characteristics.

  1. Monitoring Notch Signaling-Associated Activation of Stem Cell Niches within Injured Dental Pulp.

    Science.gov (United States)

    Mitsiadis, Thimios A; Catón, Javier; Pagella, Pierfrancesco; Orsini, Giovanna; Jimenez-Rojo, Lucia

    2017-01-01

    Dental pulp stem/progenitor cells guarantee tooth homeostasis, repair and regeneration throughout life. The decision between renewal and differentiation of these cells is influenced by physical and molecular interactions with stromal cells and extracellular matrix molecules forming the specialized microenvironment of dental pulp stem cell niches. Here we study the activation of putative pulp niches after tooth injury through the upregulation of Notch signaling pathway. Notch1, Notch2, and Notch3 molecules were used as markers of dental pulp stem/progenitor cells. Upon dental injury, Notch1 and Notch3 are detected in cells related to vascular structures suggesting a role of these proteins in the activation of specific pulpal perivascular niches. In contrast, a population of Notch2-positive cells that are actively proliferative is observed in the apical part of the pulp. Kinetics of these cells is followed up with a lipophilic DiI labeling, showing that apical pulp cells migrate toward the injury site where dynamic regenerative/repair events occur. The knowledge of the activation and regulation of dental pulp stem/progenitor cells within their niches in pathologic conditions may be helpful for the realization of innovative dental treatments in the near future.

  2. Cross Talk between NOTCH Signaling and Biomechanics in Human Aortic Valve Disease Pathogenesis

    Directory of Open Access Journals (Sweden)

    Richard C. Godby

    2014-12-01

    Full Text Available Aortic valve disease is a burgeoning public health problem associated with significant mortality. Loss of function mutations in NOTCH1 cause bicuspid aortic valve (BAV and calcific aortic valve disease. Because calcific nodules manifest on the fibrosa side of the cusp in low fluidic oscillatory shear stress (OSS, elucidating pathogenesis requires approaches that consider both molecular and mechanical factors. Therefore, we examined the relationship between NOTCH loss of function (LOF and biomechanical indices in healthy and diseased human aortic valve interstitial cells (AVICs. An orbital shaker system was used to apply cyclic OSS, which mimics the cardiac cycle and hemodynamics experienced by AVICs in vivo. NOTCH LOF blocked OSS-induced cell alignment in human umbilical vein endothelial cells (HUVECs, whereas AVICs did not align when subjected to OSS under any conditions. In healthy AVICs, OSS resulted in decreased elastin (ELN and α-SMA (ACTA2. NOTCH LOF was associated with similar changes, but in diseased AVICs, NOTCH LOF combined with OSS was associated with increased α-SMA expression. Interestingly, AVICs showed relatively higher expression of NOTCH2 compared to NOTCH1. Biomechanical interactions between endothelial and interstitial cells involve complex NOTCH signaling that contributes to matrix homeostasis in health and disorganization in disease.

  3. Promotion of mouse ameloblast proliferation by Lgr5 mediated integrin signaling.

    Science.gov (United States)

    Yoshida, Toshiyuki; Iwata, Takanori; Umemoto, Terumasa; Shiratsuchi, Yoshiko; Kawashima, Nobuyuki; Sugiyama, Toshihiro; Yamato, Masayuki; Okano, Teruo

    2013-09-01

    Rodent incisors grow throughout the animal's lives, and the tooth-forming cells are provided from proximal ends of the incisors where the tooth epithelium forms a stem cell niche called cervical loop. The committing cells in a cervical loop actively begin to proliferate (pre-ameloblasts), and differentiating into ameloblasts. This study showed that the lower incisors of mice null for CD61 (CD61(-/-) ), also known as integrin β3, were significantly shorter than those of the wild-type mice at 8-week-old. The protein and mRNA expressions levels of Fgfr2, Lgr5, and Notch1, which are known to be involved in pre-ameloblastic cell proliferation and stem cell maintenance, were reduced in the cervical loop of 2-week-old CD61(-/-) mice. The proliferation of pre-ameloblasts was reduced in CD61(-/-) ameloblasts. The siRNA-mediated suppression of CD61 (siCD61) reduced the proliferation of pre-ameloblastic cell line ALC, and the expression levels of Lgr5 and Notch1 were reduced by the transfection with siCD61. The suppression of Lgr5 by transfection with siLgr5 suppressed the proliferation of the ALC cells. These results suggested that CD61 signaling is required for the proper growth of the cervical loop and for the promotion of the proliferation of pre-ameloblastic cells through Lgr5. Copyright © 2013 Wiley Periodicals, Inc.

  4. Oridonin inhibits breast cancer growth and metastasis through blocking the Notch signaling

    Directory of Open Access Journals (Sweden)

    Shixin Xia

    2017-05-01

    Full Text Available Background: Oridonin is a diterpenoid isolated from Rabdosia rubescens with potent anticancer activity. The aim of our study is to investigate the role of oridonin to inhibit growth and metastasis of human breast cancer cells. Methods: The effect of oridonin on proliferation was evaluated by MTT assay, cell migration and invasion were evaluated by transwell migration and invasion assays in human breast cancer cells. The inhibitive effect of oridonin in vivo was determined by using xenografted nude mice. In addition, the expression of Notch receptors (Notch 1–4 was detected by western blot. Results: Oridonin inhibited human breast cancer cells in vitro and in vivo. In addition, oridonin significantly induced human breast cancer cells apoptosis. Furthermore, the oridonin treatment not only inhibited cancer cell migration and invasion, but more significantly, decreased the expression of Notch 1-4 protein. Conclusion: Our results suggest that the inhibitive effect of oridonin is likely to be driven by the inhibition of Notch signaling pathway and the resulting increased apoptosis.

  5. Notch signaling sustains the expression of Mcl-1 and the activity of eIF4E to promote cell survival in CLL.

    Science.gov (United States)

    De Falco, Filomena; Sabatini, Rita; Del Papa, Beatrice; Falzetti, Franca; Di Ianni, Mauro; Sportoletti, Paolo; Baldoni, Stefano; Screpanti, Isabella; Marconi, Pierfrancesco; Rosati, Emanuela

    2015-06-30

    In chronic lymphocytic leukemia (CLL), Notch1 and Notch2 signaling is constitutively activated and contributes to apoptosis resistance. We show that genetic inhibition of either Notch1 or Notch2, through small-interfering RNA, increases apoptosis of CLL cells and is associated with decreased levels of the anti-apoptotic protein Mcl-1. Thus, Notch signaling promotes CLL cell survival at least in part by sustaining Mcl-1 expression. In CLL cells, an enhanced Notch activation also contributes to the increase in Mcl-1 expression and cell survival induced by IL-4.Mcl-1 downregulation by Notch targeting is not due to reduced transcription or degradation by caspases, but in part, to increased degradation by the proteasome. Mcl-1 downregulation by Notch targeting is also accompanied by reduced phosphorylation of eukaryotic translation initiation factor 4E (eIF4E), suggesting that this protein is another target of Notch signaling in CLL cells.Overall, we show that Notch signaling sustains CLL cell survival by promoting Mcl-1 expression and eIF4E activity, and given the oncogenic role of these factors, we underscore the therapeutic potential of Notch inhibition in CLL.

  6. Timed arrays wideband and time varying antenna arrays

    CERN Document Server

    Haupt, Randy L

    2015-01-01

    Introduces timed arrays and design approaches to meet the new high performance standards The author concentrates on any aspect of an antenna array that must be viewed from a time perspective. The first chapters briefly introduce antenna arrays and explain the difference between phased and timed arrays. Since timed arrays are designed for realistic time-varying signals and scenarios, the book also reviews wideband signals, baseband and passband RF signals, polarization and signal bandwidth. Other topics covered include time domain, mutual coupling, wideband elements, and dispersion. The auth

  7. Portulaca oleracea extract can inhibit nodule formation of colon cancer stem cells by regulating gene expression of the Notch signal transduction pathway.

    Science.gov (United States)

    Jin, Heiying; Chen, Li; Wang, Shuiming; Chao, Deng

    2017-07-01

    To investigate whether Portulaca oleracea extract affects tumor formation in colon cancer stem cells and its chemotherapy sensitivity. In addition, to analyze associated genetic changes within the Notch signal transduction pathway. Serum-free cultures of colon cancer cells (HT-29) and HT-29 cancer stem cells were treated with the chemotherapeutic drug 5-fluorouracil to assess sensitivity. Injections of the stem cells were also given to BALB/c mice to confirm tumor growth and note its characteristics. In addition, the effect of different concentrations of P. oleracea extract was tested on the growth of HT-29 colon cancer cells and HT-29 cancer stem cells, as determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide method. The effects of P. oleracea extract on the expression of β-catenin, Notch1, and Notch2 in the HT-29 cells were studied using reverse transcription polymerase chain reaction and Western blotting. The tumor volume of the HT29 cells was two times larger than that of HT29 cancer stem cells. Treatment with P. oleracea extract inhibited the proliferation of both HT-29 cancer cells and HT-29 cancer stem cells at doses from 0.07 to 2.25 µg/mL. Apoptosis of HT-29 cancer cells and HT-29 cancer stem cells was assessed by flow cytometry; it was enhanced by the addition of P. oleracea extract. Finally, treatment with P. oleracea extract significantly downregulated the expression of the Notch1 and β-catenin genes in both cell types. The results of this study show that P. oleracea extract inhibits the growth of colon cancer stem cells in a dose-dependent manner. Furthermore, it inhibits the expression of the Notch1 and β-catenin genes. Taken together, this suggests that it may elicit its effects through regulatory and target genes that mediate the Notch signal transduction pathway.

  8. Einstein Equations from Varying Complexity

    Science.gov (United States)

    Czech, Bartłomiej

    2018-01-01

    A recent proposal equates the circuit complexity of a quantum gravity state with the gravitational action of a certain patch of spacetime. Since Einstein's equations follow from varying the action, it should be possible to derive them by varying complexity. I present such a derivation for vacuum solutions of pure Einstein gravity in three-dimensional asymptotically anti-de Sitter space. The argument relies on known facts about holography and on properties of tensor network renormalization, an algorithm for coarse-graining (and optimizing) tensor networks.

  9. INFLUENCE OF SUPERPLASTICIZER AND VARYING ...

    African Journals Online (AJOL)

    This paper presents the results of the study on the influence of superplasticizer and varying aggregate size on the drying shrinkage and compressive strength of laterised concrete. Four different samples of laterised concrete were made from prescribed mix ratio of 1:1:2 which include; two control specimens made with ...

  10. Optimistlik Karlovy Vary / Jaan Ruus

    Index Scriptorium Estoniae

    Ruus, Jaan, 1938-2017

    2007-01-01

    42. Karlovy Vary rahvusvahelise filmifestivali auhinnatud filmidest (žürii esimees Peter Bart). Kristallgloobuse sai Islandi-Saksamaa "Katseklaasilinn" (režii Baltasar Kormakur), parimaks režissööriks tunnistati norralane Bard Breien ("Negatiivse mõtlemise kunst"). Austraallase Michael James Rowlandi "Hea õnne teekond" sai žürii eripreemia

  11. Esmaklassiline Karlovy Vary / Jaanus Noormets

    Index Scriptorium Estoniae

    Noormets, Jaanus

    2007-01-01

    Ilmar Raagi mängufilm "Klass" võitis 42. Karlovy Vary rahvusvahelise filmifestivalil kaks auhinda - ametliku kõrvalvõistlusprogrammi "East of the West" eripreemia "Special mention" ja Euroopa väärtfilmikinode keti Europa Cinemas preemia. Ka Asko Kase lühifilmi "Zen läbi prügi linastumisest ning teistest auhinnasaajatest ning osalejatest

  12. Time-varying Crash Risk

    DEFF Research Database (Denmark)

    Christoffersen, Peter; Feunoua, Bruno; Jeon, Yoontae

    We estimate a continuous-time model with stochastic volatility and dynamic crash probability for the S&P 500 index and find that market illiquidity dominates other factors in explaining the stock market crash risk. While the crash probability is time-varying, its dynamic depends only weakly...

  13. Eestlased Karlovy Varys / J. R.

    Index Scriptorium Estoniae

    J. R.

    2007-01-01

    Ilmar Raagi mängufilm "Klass" osaleb 42. Karlovy Vary rahvusvahelise filmifestivali võistlusprogrammis "East of the West" ja Asko Kase lühimängufilm "Zen läbi prügi" on valitud festivali kõrvalprogrammi "Forum of Independents"

  14. Dll1- and dll4-mediated notch signaling are required for homeostasis of intestinal stem cells.

    Science.gov (United States)

    Pellegrinet, Luca; Rodilla, Veronica; Liu, Zhenyi; Chen, Shuang; Koch, Ute; Espinosa, Lluis; Kaestner, Klaus H; Kopan, Raphael; Lewis, Julian; Radtke, Freddy

    2011-04-01

    Ablation of Notch signaling within the intestinal epithelium results in loss of proliferating crypt progenitors due to their conversion into postmitotic secretory cells. We aimed to confirm that Notch was active in stem cells (SCs), investigate consequences of loss of Notch signaling within the intestinal SC compartment, and identify the physiologic ligands of Notch in mouse intestine. Furthermore, we investigated whether the induction of goblet cell differentiation that results from loss of Notch requires the transcription factor Krüppel-like factor 4 (Klf4). Transgenic mice that carried a reporter of Notch1 activation were used for lineage tracing experiments. The in vivo functions of the Notch ligands Jagged1 (Jag1), Delta-like1 (Dll1), Delta-like4 (Dll4), and the transcription factor Klf4 were assessed in mice with inducible, gut-specific gene targeting (Vil-Cre-ER(T2)). Notch1 signaling was found to be activated in intestinal SCs. Although deletion of Jag1 or Dll4 did not perturb the intestinal epithelium, inactivation of Dll1 resulted in a moderate increase in number of goblet cells without noticeable effects of progenitor proliferation. However, simultaneous inactivation of Dll1 and Dll4 resulted in the complete conversion of proliferating progenitors into postmitotic goblet cells, concomitant with loss of SCs (Olfm4(+), Lgr5(+), and Ascl2(+)). Klf4 inactivation did not interfere with goblet cell differentiation in adult wild-type or in Notch pathway-deficient gut. Notch signaling in SCs and progenitors is activated by Dll1 and Dll4 ligands and is required for maintenance of intestinal progenitor and SCs. Klf4 is dispensable for goblet cell differentiation in intestines of adult Notch-deficient mice. Copyright © 2011 AGA Institute. Published by Elsevier Inc. All rights reserved.

  15. Dll1- and Dll4-mediated Notch signaling is required for homeostasis of intestinal stem cells

    Science.gov (United States)

    Pellegrinet, Luca; Rodilla, Veronica; Liu, Zhenyi; Chen, Shuang; Koch, Ute; Espinosa, Lluis; Kaestner, Klaus H.; Kopan, Raphael; Lewis, Julian; Radtke, Freddy

    2011-01-01

    Background & Aims Ablation of Notch signaling within the intestinal epithelium results in loss of proliferating crypt progenitors, due to their conversion into post-mitotic secretory cells. We aimed to confirm that Notch was active in stem cells (SC), investigate consequences of loss of Notch signaling within the intestinal SC compartment, and identify the physiological ligands of Notch in mouse intestine. Furthermore, we investigated whether the induction of goblet cell differentiation that results from loss of Notch requires the transcription factor Krüppel-like factor 4 (Klf4). Methods Trasgenic mice that carried a reporter of Notch1 activation were used for lineage tracing experiments. The in vivo functions of the Notch ligands Jagged1 (Jag1), Delta-like1 (Dll1), Delta-like4 (Dll4), and the transcription factor Klf4 were assessed in mice with inducible, gut-specific gene targeting (Vil-Cre-ERT2). Results Notch1 signaling was found to be activated in intestinal SC. Although deletion of Jag1 or Dll4 did not perturb the intestinal epithelium, inactivation of Dll1 resulted in a moderate increase in number of goblet cells without noticeable effects of progenitor proliferation. However, simultaneous inactivation of Dll1 and Dll4 resulted in the complete conversion of proliferating progenitors into post-mitotic goblet cells, concomitant with loss of SC (Olfm4+, Lgr5+ and Ascl2+). Klf4 inactivation did not interfere with goblet cell differentiation in adult wild-type or in Notch pathway-deficient gut. Conclusions Notch signaling in SC and progenitors is activated by Dll1 and Dll4 ligands and is required for maintenance of intestinal progenitor and SC. Klf4 is dispensable for goblet cell differentiation in intestines of adult Notch-deficient mice. PMID:21238454

  16. Rnd3 regulates lung cancer cell proliferation through notch signaling.

    Directory of Open Access Journals (Sweden)

    Yongjun Tang

    Full Text Available Rnd3/RhoE is a small Rho GTPase involved in the regulation of different cell behaviors. Dysregulation of Rnd3 has been linked to tumorigenesis and metastasis. Lung cancers are the leading cause of cancer-related death in the West and around the world. The expression of Rnd3 and its ectopic role in non-small cell lung cancer (NSCLC remain to be explored. Here, we reported that Rnd3 was down-regulated in three NSCLC cell lines: H358, H520 and A549. The down-regulation of Rnd3 led to hyper-activation of Rho Kinase and Notch signaling. The reintroduction of Rnd3 or selective inhibition of Notch signaling, but not Rho Kinase signaling, blocked the proliferation of H358 and H520 cells. Mechanistically, Notch intracellular domain (NICD protein abundance in H358 cells was regulated by Rnd3-mediated NICD proteasome degradation. Rnd3 regulated H358 and H520 cell proliferation through a Notch1/NICD/Hes1 signaling axis independent of Rho Kinase.

  17. Loss of TGF-β Adaptor β2SP Activates Notch Signaling and SOX9 Expression in Esophageal Adenocarcinoma

    Science.gov (United States)

    Song, Shumei; Maru, Dipen M.; Ajani, Jaffer A.; Chan, Chia-Hsin; Honjo, Soichiro; Lin, Hui-Kuan; Correa, Arlene; Hofstetter, Wayne L.; Davila, Marta; Stroehlein, John; Mishra, Lopa

    2013-01-01

    TGF-β and Notch signaling pathways play important roles in regulating self-renewal of stem cells and gastrointestinal carcinogenesis. Loss of TGF-β signaling components activates Notch signaling in esophageal adenocarcinoma, but the basis for this effect has been unclear. Here we report that loss of TGF-β adapter β2SP (SPNB2) activates Notch signaling and its target SOX9 in primary fibroblasts or esophageal adenocarcinoma cells. Expression of the stem cell marker SOX9 was markedly higher in esophageal adenocarcinoma tumor tissues than normal tissues, and its higher nuclear staining in tumors correlated with poorer survival and lymph node invasion in esophageal adenocarcinoma patients. Downregulation of β2SP by lentivirus short hairpin RNA increased SOX9 transcription and expression, enhancing nuclear localization for both active Notch1 (intracellular Notch1, ICN1) and SOX9. In contrast, reintroduction into esophageal adenocarcinoma cells of β2SP and a dominant-negative mutant of the Notch coactivator mastermind-like (dnMAN) decreased SOX9 promoter activity. Tumor sphere formation and invasive capacity in vitro and tumor growth in vivo were increased in β2SP-silenced esophageal adenocarcinoma cells. Conversely, SOX9 silencing rescued the phenotype of esophageal adenocarcinoma cells with loss of β2SP. Interaction between Smad3 and ICN1 via Smad3 MH1 domain was also observed, with loss of β2SP increasing the binding between these proteins, inducing expression of Notch targets SOX9 and C-MYC, and decreasing expression of TGF-β targets p21(CDKN1A), p27 (CDKN1B), and E-cadherin. Taken together, our findings suggest that loss of β2SP switches TGF-β signaling from tumor suppression to tumor promotion by engaging Notch signaling and activating SOX9. PMID:23536563

  18. [Expression changes of Notch and nuclear factor-κB signaling pathways in the rat heart with myocardial infarction].

    Science.gov (United States)

    Jin, J L; Deng, Z T; Lyu, R G; Liu, X H; Wei, J R

    2017-06-24

    Objective: To observe the expression changes of Notch and nuclear factor-κB (NF-κB) signaling pathways in rat myocardium post myocardial infarction. Methods: Myocardial infarction was established by ligation of the left anterior descending coronary artery(MI group), sham rats (similar surgical procedure without coronary artery ligation) served as control, the rats were sacrificed at first week, 4th and 8th week after operation, the non-infarct myocardial tissue in both groups was obtained to detect the mRNA expression of Notch1, Dll4 and Hes1 by RT-PCR, the protein expression of NICD1 was detected by Western blot, the nuclear protein p65 content was detected to reflect the activation degree of NF-κB signaling in the cardiomyocytes. Results: The myocardial mRNA expression of Notch1 in MI group was significantly higher than in control group (1.68±0.35 vs. 0.47±0.12, P0.05). The mRNA expression of Dll4 and Hes1 was similar between the two groups at the three time points. NICD1 protein level was increased at the first week in MI group as compared with control group (1.31±0.33 vs.0.45±0.11, P0.05). For NF-κB activation study, the nuclear protein p65 content was higher at first week, 4th week and 8th week in MI group as compared with respective control groups (0.286±0.052 vs.0.049±0.016 (Pmyocardial infarction. Notch1 and NF-κB signaling pathways are both activated at the first week after myocardial infarction, NF-κB signaling pathway activation after myocardial infarction continues up to 8 weeks. These two signal transduction pathways may thus serve as new targets for future intervention studies to prevent heart failure.

  19. Harmonic functions with varying coefficients

    Directory of Open Access Journals (Sweden)

    Jacek Dziok

    2016-05-01

    Full Text Available Abstract Complex-valued harmonic functions that are univalent and sense preserving in the open unit disk can be written in the form f = h + g ‾ $f=h+\\overline{g}$ , where h and g are analytic. In this paper we investigate some classes of univalent harmonic functions with varying coefficients related to Janowski functions. By using the extreme points theory we obtain necessary and sufficient convolution conditions, coefficients estimates, distortion theorems, and integral mean inequalities for these classes of functions. The radii of starlikeness and convexity for these classes are also determined.

  20. Free Electron Lasers with Slowly Varying Beam and Undulator Parameters

    CERN Document Server

    Huang, Zhirong

    2005-01-01

    The performance of a free electron lasers (FEL) is affected when the electron beam energy varies alone the undulator as would be caused by vacuum pipe wakefields and/or when the undulator strength parameter is tapered in the small signal regime until FEL saturation. In this paper, we present a self-consistent theory of FELs with slowly-varying beam and undulator parameters. A general method is developed to apply the WKB approximation to the beam-radiation system by employing the adjoint eigenvector that is orthogonal to the eigenfunctions of the coupled Maxwell-Vlasov equations. This method may be useful for other slowly varying processes in beam dynamics.

  1. Robust Stabilization of Nonlinear Systems with Uncertain Varying Control Coefficient

    Directory of Open Access Journals (Sweden)

    Zaiyue Yang

    2014-01-01

    Full Text Available This paper investigates the stabilization problem for a class of nonlinear systems, whose control coefficient is uncertain and varies continuously in value and sign. The study emphasizes the development of a robust control that consists of a modified Nussbaum function to tackle the uncertain varying control coefficient. By such a method, the finite-time escape phenomenon has been prevented when the control coefficient is crossing zero and varying its sign. The proposed control guarantees the asymptotic stabilization of the system and boundedness of all closed-loop signals. The control performance is illustrated by a numerical simulation.

  2. Varying Constants, Gravitation and Cosmology.

    Science.gov (United States)

    Uzan, Jean-Philippe

    2011-01-01

    Fundamental constants are a cornerstone of our physical laws. Any constant varying in space and/or time would reflect the existence of an almost massless field that couples to matter. This will induce a violation of the universality of free fall. Thus, it is of utmost importance for our understanding of gravity and of the domain of validity of general relativity to test for their constancy. We detail the relations between the constants, the tests of the local position invariance and of the universality of free fall. We then review the main experimental and observational constraints that have been obtained from atomic clocks, the Oklo phenomenon, solar system observations, meteorite dating, quasar absorption spectra, stellar physics, pulsar timing, the cosmic microwave background and big bang nucleosynthesis. At each step we describe the basics of each system, its dependence with respect to the constants, the known systematic effects and the most recent constraints that have been obtained. We then describe the main theoretical frameworks in which the low-energy constants may actually be varying and we focus on the unification mechanisms and the relations between the variation of different constants. To finish, we discuss the more speculative possibility of understanding their numerical values and the apparent fine-tuning that they confront us with.

  3. Varying Constants, Gravitation and Cosmology

    Directory of Open Access Journals (Sweden)

    Jean-Philippe Uzan

    2011-03-01

    Full Text Available Fundamental constants are a cornerstone of our physical laws. Any constant varying in space and/or time would reflect the existence of an almost massless field that couples to matter. This will induce a violation of the universality of free fall. Thus, it is of utmost importance for our understanding of gravity and of the domain of validity of general relativity to test for their constancy. We detail the relations between the constants, the tests of the local position invariance and of the universality of free fall. We then review the main experimental and observational constraints that have been obtained from atomic clocks, the Oklo phenomenon, solar system observations, meteorite dating, quasar absorption spectra, stellar physics, pulsar timing, the cosmic microwave background and big bang nucleosynthesis. At each step we describe the basics of each system, its dependence with respect to the constants, the known systematic effects and the most recent constraints that have been obtained. We then describe the main theoretical frameworks in which the low-energy constants may actually be varying and we focus on the unification mechanisms and the relations between the variation of different constants. To finish, we discuss the more speculative possibility of understanding their numerical values and the apparent fine-tuning that they confront us with.

  4. Ehrlichia chaffeensis TRP120 Activates Canonical Notch Signaling To Downregulate TLR2/4 Expression and Promote Intracellular Survival

    Directory of Open Access Journals (Sweden)

    Taslima T. Lina

    2016-07-01

    Full Text Available Ehrlichia chaffeensis preferentially targets mononuclear phagocytes and survives through a strategy of subverting innate immune defenses, but the mechanisms are unknown. We have shown E. chaffeensis type 1 secreted tandem repeat protein (TRP effectors are involved in diverse molecular pathogen-host interactions, such as the TRP120 interaction with the Notch receptor-cleaving metalloprotease ADAM17. In the present study, we demonstrate E. chaffeensis, via the TRP120 effector, activates the canonical Notch signaling pathway to promote intracellular survival. We found that nuclear translocation of the transcriptionally active Notch intracellular domain (NICD occurs in response to E. chaffeensis or recombinant TRP120, resulting in upregulation of Notch signaling pathway components and target genes notch1, adam17, hes, and hey. Significant differences in canonical Notch signaling gene expression levels (>40% were observed during early and late stages of infection, indicating activation of the Notch pathway. We linked Notch pathway activation specifically to the TRP120 effector, which directly interacts with the Notch metalloprotease ADAM17. Using pharmacological inhibitors and small interfering RNAs (siRNAs against γ-secretase enzyme, Notch transcription factor complex, Notch1, and ADAM17, we demonstrated that Notch signaling is required for ehrlichial survival. We studied the downstream effects and found that E. chaffeensis TRP120-mediated activation of the Notch pathway causes inhibition of the extracellular signal-regulated kinase 1/2 (ERK1/2 and p38 mitogen-activated protein kinase (MAPK pathways required for PU.1 and subsequent Toll-like receptor 2/4 (TLR2/4 expression. This investigation reveals a novel mechanism whereby E. chaffeensis exploits the Notch pathway to evade the host innate immune response for intracellular survival.

  5. Time-frequency representation based on time-varying ...

    Indian Academy of Sciences (India)

    A parametric time-frequency representation is presented based on timevarying autoregressive model (TVAR), followed by applications to non-stationary vibration signal processing. The identification of time-varying model coefficients and the determination of model order, are addressed by means of neural networks and ...

  6. Local Varying-Alpha Theories

    CERN Document Server

    Barrow, John D

    2014-01-01

    In a recent paper we demonstrated how the simplest model for varying alpha may be interpreted as the effect of a dielectric material, generalized to be consistent with Lorentz invariance. Unlike normal dielectrics, such a medium cannot change the speed of light, and its dynamics obey a Klein-Gordon equation. This work immediately suggests an extension of the standard theory, even if we require compliance with Lorentz invariance. Instead of a wave equation, the dynamics may satisfy a local algebraic relation involving the permittivity and the properties of the electromagnetic field, in analogy with more conventional dielectric (but still preserving Lorentz invariance). We develop the formalism for such theories and investigate some phenomenological implications. The problem of the divergence of the classical self-energy can be solved, or at least softened, in this framework. Some interesting new cosmological solutions for the very early universe are found, including the possibility of a bounce, inflation and e...

  7. Weighted approximation with varying weight

    CERN Document Server

    Totik, Vilmos

    1994-01-01

    A new construction is given for approximating a logarithmic potential by a discrete one. This yields a new approach to approximation with weighted polynomials of the form w"n"(" "= uppercase)P"n"(" "= uppercase). The new technique settles several open problems, and it leads to a simple proof for the strong asymptotics on some L p(uppercase) extremal problems on the real line with exponential weights, which, for the case p=2, are equivalent to power- type asymptotics for the leading coefficients of the corresponding orthogonal polynomials. The method is also modified toyield (in a sense) uniformly good approximation on the whole support. This allows one to deduce strong asymptotics in some L p(uppercase) extremal problems with varying weights. Applications are given, relating to fast decreasing polynomials, asymptotic behavior of orthogonal polynomials and multipoint Pade approximation. The approach is potential-theoretic, but the text is self-contained.

  8. Diurnally-Varying Lunar Hydration

    Science.gov (United States)

    Hendrix, A. R.; Hurley, D.; Retherford, K. D.; Mandt, K.; Greathouse, T. K.; Farrell, W. M.; Vilas, F.

    2016-12-01

    Dayside, non-polar lunar hydration signatures have been observed by a handful of instruments and present insights into the lunar water cycle. In this study, we utilize the unique measurements from the current Lunar Reconnaissance Orbiter (LRO) mission to study the phenomenon of diurnally-varying dayside lunar hydration. The Lyman Alpha Mapping Project (LAMP) onboard LRO senses a strong far-ultraviolet water absorption edge indicating hydration in small abundances in the permanently shadowed regions as well as on the lunar dayside. We report on diurnal variability in hydration in different terrain types. We investigate the importance of different sources of hydration, including solar wind bombardment and meteoroid bombardment, by observing trends during magnetotail and meteor stream crossings.

  9. Nonstationary weak signal detection based on normalization ...

    Indian Academy of Sciences (India)

    ... than the traditional stochastic resonance. The method develops the area of time-varying signal detection with stochastic resonance and presents new strategy for detection and denoising of a time-varying signal. It can be expected to be widely used in the areas of aperiodic signal processing, radar communication,etc ...

  10. Activated Notch signaling cascade is correlated with stem cell differentiation toward absorptive progenitors after massive small bowel resection in a rat.

    Science.gov (United States)

    Sukhotnik, Igor; Coran, Arnold G; Pollak, Yulia; Kuhnreich, Eviatar; Berkowitz, Drora; Saxena, Amulya K

    2017-09-01

    Notch signaling is thought to act to drive cell versification in the lining of the small intestine. The purpose of the present study was to evaluate the role of the Notch signaling pathway in stem cell differentiation in the late stages of intestinal adaptation after massive small bowel resection in a rat. Male Sprague-Dawley rats were randomly assigned to one of two experimental groups of eight rats each: Sham rats underwent bowel transection and reanastomosis, while SBS rats underwent 75% small bowel resection. Rats were euthanized on day 14 Illumina's Digital Gene Expression (DGE) analysis was used to determine Notch signaling gene expression profiling. Notch-related gene and protein expression was determined using real-time PCR, Western blot analysis, and immunohistochemistry. From seven investigated Notch-related (by DGE analysis) genes, six genes were upregulated in SBS vs. control animals with a relative change in gene expression level of 20% or more. A significant upregulation of Notch signaling-related genes in resected animals was accompanied by a significant increase in Notch-1 protein levels (Western blot analysis) and a significant increase in the number of Notch1 and Hes1 (target gene)-positive cells (immunohistochemistry) compared with sham animals. Evaluation of cell differentiation has shown a strong increase in total number of absorptive cells (unchanged secretory cells) compared with control rats. In conclusion, 2 wk after bowel resection in rats, stimulated Notch signaling directs the crypt cell population toward absorptive progenitors.NEW & NOTEWORTHY This study provides novel insight into the mechanisms of cell proliferation following massive small bowel resection. We show that 2 wk after bowel resection in rats, enhanced stem cell activity was associated with stimulated Notch signaling pathway. We demonstrate that activated Notch signaling cascade directs the crypt cell population toward absorptive progenitors. Copyright © 2017 the American

  11. Notch signaling modulates hypoxia-induced neuroendocrine differentiation of human prostate cancer cells.

    Science.gov (United States)

    Danza, Giovanna; Di Serio, Claudia; Rosati, Fabiana; Lonetto, Giuseppe; Sturli, Niccolò; Kacer, Doreen; Pennella, Antonio; Ventimiglia, Giuseppina; Barucci, Riccardo; Piscazzi, Annamaria; Prudovsky, Igor; Landriscina, Matteo; Marchionni, Niccolò; Tarantini, Francesca

    2012-02-01

    Prostate carcinoma is among the most common causes of cancer-related death in men, representing 15% of all male malignancies in developed countries. Neuroendocrine differentiation (NED) has been associated with tumor progression, poor prognosis, and with the androgen-independent status. Currently, no successful therapy exists for advanced, castration-resistant disease. Because hypoxia has been linked to prostate cancer progression and unfavorable outcome, we sought to determine whether hypoxia would impact the degree of neuroendocrine differentiation of prostate cancer cells in vitro. Exposure of LNCaP cells to low oxygen tension induced a neuroendocrine phenotype, associated with an increased expression of the transcription factor neurogenin3 and neuroendocrine markers, such as neuron-specific enolase, chromogranin A, and β3-tubulin. Moreover, hypoxia triggered a significant decrease of Notch 1 and Notch 2 mRNA and protein expression, with subsequent downregulation of Notch-mediated signaling, as shown by reduced levels of the Notch target genes, Hes1 and Hey1. NED was promoted by attenuation of Hes1 transcription, as cells expressing a dominant-negative form of Hes1 displayed increased levels of neuroendocrine markers under normoxic conditions. Although hypoxia downregulated Notch 1 and Notch 2 mRNA transcription and receptor activation also in the androgen-independent cell lines, PC-3 and Du145, it did not change the extent of NED in these cultures, suggesting that androgen sensitivity may be required for transdifferentiation to occur. Hypoxia induces NED of LNCaP cells in vitro, which seems to be driven by the inhibition of Notch signaling with subsequent downregulation of Hes1 transcription. ©2011 AACR.

  12. NOTCH SIGNALLING MODULATES HYPOXIA-INDUCED NEUROENDOCRINE DIFFERENTIATION OF HUMAN PROSTATE CANCER CELLS

    Science.gov (United States)

    Danza, Giovanna; Di Serio, Claudia; Rosati, Fabiana; Lonetto, Giuseppe; Sturli, Niccolò; Kacer, Doreen; Pennella, Antonio; Ventimiglia, Giuseppina; Barucci, Riccardo; Piscazzi, Annamaria; Prudovsky, Igor; Landriscina, Matteo; Marchionni, Niccolò; Tarantini, Francesca

    2012-01-01

    Prostate carcinoma is among the most common causes of cancer-related death in men, representing 15% of all male malignancies in developed countries. Neuroendocrine differentiation has been associated with tumor progression, poor prognosis and with the androgen-independent status. Currently, no successful therapy exists for advanced, castration-resistant disease. Because hypoxia has been linked to prostate cancer progression and unfavourable outcome, we sought to determine whether hypoxia would impact the degree of neuroendocrine differentiation of prostate cancer cells, in vitro. Results exposure of LNCaP cells to low oxygen tension induced a neuroendocrine phenotype, associated with an increased expression of the transcription factor neurogenin3 and neuroendocrine markers, such as neuron-specific enolase, chromogranin A and β3-tubulin. Moreover, hypoxia triggered a significant decrease of Notch 1 and Notch 2 mRNA and protein expression, with subsequent down regulation of Notch-mediated signalling, as demonstrated by reduced levels of the Notch target genes, Hes1 and Hey1. Neuroendocrine differentiation was promoted by attenuation of Hes1 transcription, as cells expressing a dominant negative form of Hes1 displayed increased levels of neuroendocrine markers under normoxic conditions. Although hypoxia down regulated Notch 1 and Notch 2 mRNA transcription and receptor activation also in the androgen independent cell lines, PC3 and Du145, it did not change the extent of NE differentiation in these cultures, suggesting that androgen sensitivity may be required for transdifferentiation to occur. Conclusions hypoxia induces neuroendocrine differentiation of LNCaP cells in vitro, which appears to be driven by the inhibition of Notch signalling with subsequent down-regulation of Hes1 transcription. PMID:22172337

  13. Signal Words

    Science.gov (United States)

    SIGNAL WORDS TOPIC FACT SHEET NPIC fact sheets are designed to answer questions that are commonly asked by the ... making decisions about pesticide use. What are Signal Words? Signal words are found on pesticide product labels, ...

  14. Gait phase varies over velocities.

    Science.gov (United States)

    Liu, Yancheng; Lu, Kun; Yan, Songhua; Sun, Ming; Lester, D Kevin; Zhang, Kuan

    2014-02-01

    We sought to characterize the percent (PT) of the phases of a gait cycle (GC) as velocity changes to establish norms for pathological gait characteristics with higher resolution technology. Ninety five healthy subjects (49 males and 46 females with age 34.9 ± 11.8 yrs, body weight 64.0 ± 11.7 kg and BMI 23.5 ± 3.6) were enrolled and walked comfortably on a 10-m walkway at self-selected slower, normal, and faster velocities. Walking was recorded with a high speed camera (250 frames per second) and the eight phases of a GC were determined by examination of individual frames for each subject. The correlation coefficients between the mean PT of the phases of the three velocities gaits and PT defined by previous publications were all greater than 0.99. The correlation coefficient between velocity and PT of gait phases is -0.83 for loading response (LR), -0.75 for mid stance (MSt), and -0.84 for pre-swing (PSw). While the PT of the phases of three velocities from this study are highly correlated with PT described by Dr. Jacquenlin Perry decades ago, actual PT of each phase varied amongst these individuals with the largest coefficient variation of 24.31% for IC with slower velocity. From slower to faster walk, the mean PT of MSt diminished from 35.30% to 25.33%. High resolution recording revealed ambiguity of some gait phase definitions, and these data may benefit GC characterization of normal and pathological gait in clinical practice. The study results indicate that one should consider individual variations and walking velocity when evaluating gaits of subjects using standard gait phase classification. Copyright © 2013 Elsevier B.V. All rights reserved.

  15. Acoustic Signals and Systems

    DEFF Research Database (Denmark)

    2008-01-01

    The Handbook of Signal Processing in Acoustics will compile the techniques and applications of signal processing as they are used in the many varied areas of Acoustics. The Handbook will emphasize the interdisciplinary nature of signal processing in acoustics. Each Section of the Handbook...... will present topics on signal processing which are important in a specific area of acoustics. These will be of interest to specialists in these areas because they will be presented from their technical perspective, rather than a generic engineering approach to signal processing. Non-specialists, or specialists...... from different areas, will find the self-contained chapters accessible and will be interested in the similarities and differences between the approaches and techniques used in different areas of acoustics....

  16. Autophagy is involved in mouse kidney development and podocyte differentiation regulated by Notch signalling.

    Science.gov (United States)

    Zhang, Chuyue; Li, Wen; Wen, Junkai; Yang, Zhuo

    2017-07-01

    Podocyte dysfunction results in glomerular diseases accounted for 90% of end-stage kidney disease. The evolutionarily conserved Notch signalling makes a crucial contribution in podocyte development and function. However, the underlying mechanism of Notch pathway modulating podocyte differentiation remains less obvious. Autophagy, reported to be related with Notch signalling pathways in different animal models, is regarded as a possible participant during podocyte differentiation. Here, we found the dynamic changes of Notch1 were coincided with autophagy: they both increased during kidney development and podocyte differentiation. Intriguingly, when Notch signalling was down-regulated by DAPT, autophagy was greatly diminished, and differentiation was also impaired. Further, to better understand the relationship between Notch signalling and autophagy in podocyte differentiation, rapamycin was added to enhance autophagy levels in DAPT-treated cells, and as a result, nephrin was recovered and DAPT-induced injury was ameliorated. Therefore, we put forward that autophagy is involved in kidney development and podocyte differentiation regulated by Notch signalling. © 2017 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

  17. Matching Value Propositions with Varied Customer Needs

    DEFF Research Database (Denmark)

    Heikka, Eija-Liisa; Frandsen, Thomas; Hsuan, Juliana

    2018-01-01

    Organizations seek to manage varied customer segments using varied value propositions. The ability of a knowledge-intensive business service (KIBS) provider to formulate value propositions into attractive offerings to varied customers becomes a competitive advantage. In this specific business bas...

  18. Topological signal processing

    CERN Document Server

    Robinson, Michael

    2014-01-01

    Signal processing is the discipline of extracting information from collections of measurements. To be effective, the measurements must be organized and then filtered, detected, or transformed to expose the desired information.  Distortions caused by uncertainty, noise, and clutter degrade the performance of practical signal processing systems. In aggressively uncertain situations, the full truth about an underlying signal cannot be known.  This book develops the theory and practice of signal processing systems for these situations that extract useful, qualitative information using the mathematics of topology -- the study of spaces under continuous transformations.  Since the collection of continuous transformations is large and varied, tools which are topologically-motivated are automatically insensitive to substantial distortion. The target audience comprises practitioners as well as researchers, but the book may also be beneficial for graduate students.

  19. Error analysis for RADAR neighbor matching localization in linear logarithmic strength varying Wi-Fi environment

    National Research Council Canada - National Science Library

    Zhou, Mu; Tian, Zengshan; Xu, Kunjie; Yu, Xiang; Wu, Haibo

    2014-01-01

    ...) in logarithmic received signal strength (RSS) varying Wi-Fi environment. To the best of our knowledge, little comprehensive analysis work has appeared on the error performance of neighbor matching localization with respect to the deployment of RPs...

  20. Error Analysis for RADAR Neighbor Matching Localization in Linear Logarithmic Strength Varying Wi-Fi Environment

    National Research Council Canada - National Science Library

    Zhou, Mu; Tian, Zengshan; Xu, Kunjie; Yu, Xiang; Wu, Haibo

    2014-01-01

    ...) in logarithmic received signal strength (RSS) varying Wi-Fi environment. To the best of our knowledge, little comprehensive analysis work has appeared on the error performance of neighbor matching localization with respect to the deployment of RPs...

  1. Expression of conserved signalling pathway genes during ...

    Indian Academy of Sciences (India)

    Perturbing these pathways can result in severe and possibly lethal developmental phenotypes often due to primary cardiovascular defects. We report that during early spontaneous differentiation of R1 cells, Notch-1 and the Wnt target Brachyury are active whereas the Shh receptor is not detected. This expression pattern is ...

  2. Signaling aggression.

    Science.gov (United States)

    van Staaden, Moira J; Searcy, William A; Hanlon, Roger T

    2011-01-01

    From psychological and sociological standpoints, aggression is regarded as intentional behavior aimed at inflicting pain and manifested by hostility and attacking behaviors. In contrast, biologists define aggression as behavior associated with attack or escalation toward attack, omitting any stipulation about intentions and goals. Certain animal signals are strongly associated with escalation toward attack and have the same function as physical attack in intimidating opponents and winning contests, and ethologists therefore consider them an integral part of aggressive behavior. Aggressive signals have been molded by evolution to make them ever more effective in mediating interactions between the contestants. Early theoretical analyses of aggressive signaling suggested that signals could never be honest about fighting ability or aggressive intentions because weak individuals would exaggerate such signals whenever they were effective in influencing the behavior of opponents. More recent game theory models, however, demonstrate that given the right costs and constraints, aggressive signals are both reliable about strength and intentions and effective in influencing contest outcomes. Here, we review the role of signaling in lieu of physical violence, considering threat displays from an ethological perspective as an adaptive outcome of evolutionary selection pressures. Fighting prowess is conveyed by performance signals whose production is constrained by physical ability and thus limited to just some individuals, whereas aggressive intent is encoded in strategic signals that all signalers are able to produce. We illustrate recent advances in the study of aggressive signaling with case studies of charismatic taxa that employ a range of sensory modalities, viz. visual and chemical signaling in cephalopod behavior, and indicators of aggressive intent in the territorial calls of songbirds. Copyright © 2011 Elsevier Inc. All rights reserved.

  3. Notch signaling and progenitor/ductular reaction in steatohepatitis.

    Directory of Open Access Journals (Sweden)

    Carola M Morell

    Full Text Available Persistent hepatic progenitor cells (HPC activation resulting in ductular reaction (DR is responsible for pathologic liver repair in cholangiopathies. Also, HPC/DR expansion correlates with fibrosis in several chronic liver diseases, including steatohepatitis. Increasing evidence indicates Notch signaling as a key regulator of HPC/DR response in biliary and more in general liver injuries. Therefore, we aimed to investigate the role of Notch during HPC/DR activation in a mouse model of steatohepatitis.Steatohepatitis was generated using methionine-choline deficient (MCD diet. For hepatocyte lineage tracing, R26R-YFP mice were infected with AAV8-TBG-Cre.MCD diet promoted a strong HPC/DR response that progressively diffused in the lobule, and correlated with increased fibrosis and TGF-β1 expression. Notch signaling was unchanged in laser-capture microdissected HPC/DR, whereas Notch receptors were down regulated in hepatocytes. However, in-vivo lineage tracing experiments identified discrete hepatocytes showing Notch-1 activation and expressing (the Notch-dependent Sox9. Stimulation of AML-12 hepatocyte-cell line with immobilized Jag1 induced Sox9 and down-regulated albumin and BSEP expression. TGF-β1 treatment in primary hepatic stellate cells (HSC induced Jag1 expression. In MCD diet-fed mice, αSMA-positive HSC were localized around Sox9 expressing hepatocytes, suggesting that Notch activation in hepatocytes was promoted by TGF-β1 stimulated HSC. In-vivo Notch inhibition reduced HPC response and fibrosis progression.Our data suggest that Notch signaling is an important regulator of DR and that in steatohepatitis, hepatocytes exposed to Jag1-positive HSC, contribute to pathologic DR by undergoing Notch-mediated differentiation towards an HPC-like phenotype. Given the roles of Notch in fibrosis and liver cancer, these data suggest mesenchymal expression of Jag1 as an alternative therapeutic target.

  4. Nonstationary weak signal detection based on normalization ...

    Indian Academy of Sciences (India)

    Haibin Zhang

    model performs well in the detection of a time-varying signal with background noise for denoising and signal recovery. We take the fitness ..... The amplitude of signal and noise are amplified ffiffiffiffi b a3 q. -fold at the same time. ...... This work was supported in part by the National Natural. Science Foundation of China with ...

  5. Behavioral Signal Processing: Deriving Human Behavioral Informatics From Speech and Language: Computational techniques are presented to analyze and model expressed and perceived human behavior-variedly characterized as typical, atypical, distressed, and disordered-from speech and language cues and their applications in health, commerce, education, and beyond.

    Science.gov (United States)

    Narayanan, Shrikanth; Georgiou, Panayiotis G

    2013-02-07

    The expression and experience of human behavior are complex and multimodal and characterized by individual and contextual heterogeneity and variability. Speech and spoken language communication cues offer an important means for measuring and modeling human behavior. Observational research and practice across a variety of domains from commerce to healthcare rely on speech- and language-based informatics for crucial assessment and diagnostic information and for planning and tracking response to an intervention. In this paper, we describe some of the opportunities as well as emerging methodologies and applications of human behavioral signal processing (BSP) technology and algorithms for quantitatively understanding and modeling typical, atypical, and distressed human behavior with a specific focus on speech- and language-based communicative, affective, and social behavior. We describe the three important BSP components of acquiring behavioral data in an ecologically valid manner across laboratory to real-world settings, extracting and analyzing behavioral cues from measured data, and developing models offering predictive and decision-making support. We highlight both the foundational speech and language processing building blocks as well as the novel processing and modeling opportunities. Using examples drawn from specific real-world applications ranging from literacy assessment and autism diagnostics to psychotherapy for addiction and marital well being, we illustrate behavioral informatics applications of these signal processing techniques that contribute to quantifying higher level, often subjectively described, human behavior in a domain-sensitive fashion.

  6. Mutations in TSPEAR, Encoding a Regulator of Notch Signaling, Affect Tooth and Hair Follicle Morphogenesis.

    Directory of Open Access Journals (Sweden)

    Alon Peled

    2016-10-01

    Full Text Available Despite recent advances in our understanding of the pathogenesis of ectodermal dysplasias (EDs, the molecular basis of many of these disorders remains unknown. In the present study, we aimed at elucidating the genetic basis of a new form of ED featuring facial dysmorphism, scalp hypotrichosis and hypodontia. Using whole exome sequencing, we identified 2 frameshift and 2 missense mutations in TSPEAR segregating with the disease phenotype in 3 families. TSPEAR encodes the thrombospondin-type laminin G domain and EAR repeats (TSPEAR protein, whose function is poorly understood. TSPEAR knock-down resulted in altered expression of genes known to be regulated by NOTCH and to be involved in murine hair and tooth development. Pathway analysis confirmed that down-regulation of TSPEAR in keratinocytes is likely to affect Notch signaling. Accordingly, using a luciferase-based reporter assay, we showed that TSPEAR knock-down is associated with decreased Notch signaling. In addition, NOTCH1 protein expression was reduced in patient scalp skin. Moreover, TSPEAR silencing in mouse hair follicle organ cultures was found to induce apoptosis in follicular epithelial cells, resulting in decreased hair bulb diameter. Collectively, these observations indicate that TSPEAR plays a critical, previously unrecognized role in human tooth and hair follicle morphogenesis through regulation of the Notch signaling pathway.

  7. Notching on cancer’s door: Notch signaling in brain tumors

    Directory of Open Access Journals (Sweden)

    Marcin eTeodorczyk

    2015-01-01

    Full Text Available Notch receptors play an essential role in the regulation of central cellular processes during embryonic and postnatal development. The mammalian genome encodes for four Notch paralogs (Notch 1-4, which are activated by three Delta-like (Dll1/3/4 and two Serrate-like (Jagged1/2 ligands. Further, non-canonical Notch ligands such as EGFL7 have been identified and serve mostly as antagonists of Notch signaling. The Notch pathway prevents neuronal differentiation in the central nervous system by driving neural stem cell maintenance and commitment of neural progenitor cells into the glial lineage. Notch is therefore often implicated in the development of brain tumors, as tumor cells share various characteristics with neural stem and progenitor cells. Notch receptors are overexpressed in gliomas and their oncogenicity has been confirmed by gain- and loss-of-function studies in vitro and in vivo. To this end, special attention is paid to the impact of Notch signaling on stem-like brain tumor-propagating cells as these cells contribute to growth, survival, invasion and recurrence of brain tumors. Based on the outcome of ongoing studies in vivo, Notch-directed therapies such as γ secretase inhibitors and blocking antibodies have entered and completed various clinical trials. This review summarizes the current knowledge on Notch signaling in brain tumor formation and therapy.

  8. Notch signaling regulates formation of the three-dimensional architecture of intrahepatic bile ducts in mice.

    Science.gov (United States)

    Sparks, Erin E; Huppert, Kari A; Brown, Melanie A; Washington, M Kay; Huppert, Stacey S

    2010-04-01

    Alagille syndrome, a chronic hepatobiliary disease, is characterized by paucity of intrahepatic bile ducts (IHBDs). To determine the impact of Notch signaling specifically on IHBD arborization, we studied the influence of both chronic gain and loss of Notch function on the intact three-dimensional IHBD structure using a series of mutant mouse models and a resin casting method. Impaired Notch signaling in bipotential hepatoblast progenitor cells (BHPCs) dose-dependently decreased the density of peripheral IHBDs, whereas activation of Notch1 results in an increased density of peripheral IHBDs. Although Notch2 has a dominant role in IHBD formation, there is also a redundant role for other Notch receptors in determining the density of peripheral IHBDs. Because changes in IHBD density do not appear to be due to changes in cellular proliferation of bile duct progenitors, we suggest that Notch plays a permissive role in cooperation with other factors to influence lineage decisions of BHPCs and sustain peripheral IHBDs. There is a threshold requirement for Notch signaling at multiple steps, including IHBD tubulogenesis and maintenance, during hepatic development that determines the density of three-dimensional peripheral IHBD architecture.

  9. Song trait similarity in great tits varies with social structure.

    Directory of Open Access Journals (Sweden)

    Lysanne Snijders

    Full Text Available For many animals, long-range signalling is essential to maintain contact with conspecifics. In territorial species, individuals often have to balance signalling towards unfamiliar potential competitors (to solely broadcast territory ownership with signalling towards familiar immediate neighbours (to also maintain so-called "dear enemy" relations. Hence, to understand how signals evolve due to these multilevel relationships, it is important to understand how general signal traits vary in relation to the overall social environment. For many territorial songbirds dawn is a key signalling period, with several neighbouring individuals singing simultaneously without immediate conflict. In this study we tested whether sharing a territory boundary, rather than spatial proximity, is related to similarity in dawn song traits between territorial great tits (Parus major in a wild personality-typed population. We collected a large dataset of automatized dawn song recordings from 72 unique male great tits, during the fertile period of their mate, and compared specific song traits between neighbours and non-neighbours. We show here that both song rate and start time of dawn song were repeatable song traits. Moreover, neighbours were significantly more dissimilar in song rate compared to non-neighbours, while there was no effect of proximity on song rate similarity. Additionally, similarity in start time of dawn song was unrelated to sharing a territory boundary, but birds were significantly more similar in start time of dawn song when they were breeding in close proximity of each other. We suggest that the dissimilarity in dawn song rate between neighbours is either the result of neighbouring great tits actively avoiding similar song rates to possibly prevent interference, or a passive consequence of territory settlement preferences relative to the types of neighbours. Neighbourhood structuring is therefore likely to be a relevant selection pressure shaping

  10. Ultrasonic Adaptive Detection for Aerospace Components with Varying Thickness

    Directory of Open Access Journals (Sweden)

    Zhen Xiao

    2017-01-01

    Full Text Available Automatic inspection of microdefects located in the aerospace components is difficult due to the imprecise scanning trajectory, especially for those specimens with varying thickness. In this paper, a new ultrasonic nondestructive testing (NDT system using the robotic scanning trajectory is constructed for inspecting turbine blades. Additionally, an approach based on the analysis of ultrasonic signals is proposed to calibrate the trajectory; the ultrasonic image based on the threshold function represents the distribution of inner defects when the following gate is used to track the flaw echo. Therefore, the characteristic parameters of the flaw echo signals are easy to be discriminated if the reflection waves are stable in the time domain. Experimental result verified the effective and feasibility of the proposed approach; the distribution of inner defects can be shown with a higher resolution than other NDT methods when robotic orientation is correct at each point of scanning trajectory. Furthermore, the feature signals can be tracked more accurately during the ultrasonic signal processing if the ultrasonic distance was considered as a calibration coefficient of positional matrix. The proposed ultrasonic adaptive detection is adapted to complex geometric structure with a minimum resolution of equivalent diameter of the inner flaw being 0.15 millimeters.

  11. Tavatult jahe Karlovy Vary / Jaanus Noormets

    Index Scriptorium Estoniae

    Noormets, Jaanus

    2011-01-01

    1.-10. juulini toimunud Karlovy Vary 46. filmifestivalist (muusikafilmide alajaotuses näidati Marianne Kõrveri dokumentaalfilmi "Erkki-Sven Tüür: 7 etüüdi piltides" (2010) programmis "A Musical Odyssey")

  12. Eesti film võistleb Karlovy Varys

    Index Scriptorium Estoniae

    2008-01-01

    8. juulil esilinastub Karlovy Vary filmifestivalil Rene Vilbre noortefilm "Mina olin siin", mille aluseks on Sass Henno romaan "Mina olin siin. Esimene arest", stsenaariumi kirjutas Ilmar Raag. Film võistleb võistlusprogrammis "East of the West"

  13. Rumor Detection over Varying Time Windows

    National Research Council Canada - National Science Library

    Sejeong Kwon; Meeyoung Cha; Kyomin Jung

    2017-01-01

      This study determines the major difference between rumors and non-rumors and explores rumor classification performance levels over varying time windows--from the first three days to nearly two months...

  14. Compilation of Instantaneous Source Functions for Varying ...

    African Journals Online (AJOL)

    Compilation of Instantaneous Source Functions for Varying Architecture of a Layered Reservoir with Mixed Boundaries and Horizontal Well Completion Part IV: Normal and Inverted Letter 'h' and 'H' Architecture.

  15. Compilation of Instantaneous Source Functions for Varying ...

    African Journals Online (AJOL)

    Compilation of Instantaneous Source Functions for Varying Architecture of a Layered Reservoir with Mixed Boundaries and Horizontal Well Completion Part III: B-Shaped Architecture with Vertical Well in the Upper Layer.

  16. Arthritis Mechanisms May Vary by Joint

    Science.gov (United States)

    ... Issues Subscribe August 2016 Print this issue Arthritis Mechanisms May Vary by Joint En español Send us ... joints have unique patterns of chemical tags—called epigenetic markers—that differ between rheumatoid arthritis and osteoarthritis. ...

  17. Naringin Stimulates Osteogenic Differentiation of Rat Bone Marrow Stromal Cells via Activation of the Notch Signaling Pathway

    Directory of Open Access Journals (Sweden)

    Guo-yong Yu

    2016-01-01

    Full Text Available Naringin is a major flavonoid found in grapefruit and is an active compound extracted from the Chinese herbal medicine Rhizoma Drynariae. Naringin is a potent stimulator of osteogenic differentiation and has potential application in preventing bone loss. However, the signaling pathway underlying its osteogenic effect remains unclear. We hypothesized that the osteogenic activity of naringin involves the Notch signaling pathway. Rat bone marrow stromal cells (BMSCs were cultured in osteogenic medium containing-naringin, with or without DAPT (an inhibitor of Notch signaling, the effects on ALP activity, calcium deposits, osteogenic genes (ALP, BSP, and cbfa1, adipogenic maker gene PPARγ2 levels, and Notch expression were examined. We found that naringin dose-dependently increased ALP activity and Alizarin red S staining, and treatment at the optimal concentration (50 μg/mL increased mRNA levels of osteogenic genes and Notch1 expression, while decreasing PPARγ2 mRNA levels. Furthermore, treatment with DAPT partly reversed effects of naringin on BMSCs, as judged by decreases in naringin-induced ALP activity, calcium deposits, and osteogenic genes expression, as well as upregulation of PPARγ2 mRNA levels. These results suggest that the osteogenic effect of naringin partly involves the Notch signaling pathway.

  18. Varying flexibilities in systems of organised decentralisation

    DEFF Research Database (Denmark)

    Ilsøe, Anna; Andersen, Søren Kaj

    be while the response of the German system should rather be interpreted as a reactive organised decentralisation. 3) The varying regulation of working time flexibility in Germany and Denmark implies varying risks in the regulation. In Germany lacking competencies in small or medium-sized companies lead...... to this paradox a qualitative study of working time regulation in the metal industry in Denmark and Germany was performed in the spring of 2005. In addition to five case studies of company-based agreements in Denmark and Germany (Baden-Württemberg) the study consisted of analysing statistical data, legislative...

  19. Varying G. [in Einstein gravitation theory

    Science.gov (United States)

    Canuto, V.; Hsieh, S.-H.; Owen, J. R.

    1979-01-01

    The problem of the variation of the gravitational constant with cosmological time is critically analyzed. Since Einstein's equation does not allow G to vary on any time scale, no observational data can be analyzed within the context of the standard theory. The recently proposed scale covariant theory, which allows (but does not demand) G to vary, and which has been shown to have passed several standard cosmological tests, is employed to discuss some recent nonnull observational results which indicate a time variation of G.

  20. Sensor trustworthiness in uncertain time varying stochastic environments

    Science.gov (United States)

    Verma, Ajay; Fernandes, Ronald; Vadakkeveedu, Kalyan

    2011-06-01

    Persistent surveillance applications require unattended sensors deployed in remote regions to track and monitor some physical stimulant of interest that can be modeled as output of time varying stochastic process. However, the accuracy or the trustworthiness of the information received through a remote and unattended sensor and sensor network cannot be readily assumed, since sensors may get disabled, corrupted, or even compromised, resulting in unreliable information. The aim of this paper is to develop information theory based metric to determine sensor trustworthiness from the sensor data in an uncertain and time varying stochastic environment. In this paper we show an information theory based determination of sensor data trustworthiness using an adaptive stochastic reference sensor model that tracks the sensor performance for the time varying physical feature, and provides a baseline model that is used to compare and analyze the observed sensor output. We present an approach in which relative entropy is used for reference model adaptation and determination of divergence of the sensor signal from the estimated reference baseline. We show that that KL-divergence is a useful metric that can be successfully used in determination of sensor failures or sensor malice of various types.

  1. VISAR fringe analysis under extreme spatially varying shock loading

    Science.gov (United States)

    Erskine, David; Fratanduono, Dayne

    2017-06-01

    Many VISAR velocity interferometers employ a streak camera to record fringes along the spatial axis (Y) of a target, versus time. When the shock loading (thus velocity history) varies rapidly versus Y, the fringe analysis challenges traditional algorithms since the Y-spacing of fringes can vary strongly with Y, and be significantly different than the uniform pre-shock (bias) spacing. For traditional colum-by-column analysis the intensity signal shape would be a sinusoid with rapidly varying frequency (chirped), which can confuse a traditional algorithm expecting a monochromatic peak in Fourier space. And for a traditional push-pull row-by-row approach, the phase steps are irregular. We describe preliminary success in analyzing such data in simulation. We find it useful to (a) separate the nonfringing component from the data early; (b) maximize linearity of a plot of fringing magnitude versus nonfringing intensity to choose optimal weight values; (c) when using a row-by-row approach sampling 0, 90, 180, and 270 degrees phase we add a fifth sample at 360 degrees, which is averaged with the 0 degree sample and replaces it. This increases the robustness to variable phase step (following P. Hariharan). The pre-shock and post-shock regions are separately processed/concatenated. Prepared by LLNL under Contract DE-AC52-07NA27344.

  2. Neural processing of reward magnitude under varying attentional demands.

    Science.gov (United States)

    Stoppel, Christian Michael; Boehler, Carsten Nicolas; Strumpf, Hendrik; Heinze, Hans-Jochen; Hopf, Jens-Max; Schoenfeld, Mircea Ariel

    2011-04-06

    Central to the organization of behavior is the ability to represent the magnitude of a prospective reward and the costs related to obtaining it. Therein, reward-related neural activations are discounted in dependence of the effort required to resolve a given task. Varying attentional demands of the task might however affect reward-related neural activations. Here we employed fMRI to investigate the neural representation of expected values during a monetary incentive delay task with varying attentional demands. Following a cue, indicating at the same time the difficulty (hard/easy) and the reward magnitude (high/low) of the upcoming trial, subjects performed an attention task and subsequently received feedback about their monetary reward. Consistent with previous results, activity in anterior-cingulate, insular/orbitofrontal and mesolimbic regions co-varied with the anticipated reward-magnitude, but also with the attentional requirements of the task. These activations occurred contingent on action-execution and resembled the response time pattern of the subjects. In contrast, cue-related activations, signaling the forthcoming task-requirements, were only observed within attentional control structures. These results suggest that anticipated reward-magnitude and task-related attentional demands are concurrently processed in partially overlapping neural networks of anterior-cingulate, insular/orbitofrontal, and mesolimbic regions. Copyright © 2011 Elsevier B.V. All rights reserved.

  3. Gibberellin signaling.

    Science.gov (United States)

    Hartweck, Lynn M

    2008-12-01

    This review covers recent advances in gibberellin (GA) signaling. GA signaling is now understood to hinge on DELLA proteins. DELLAs negatively regulate GA response by activating the promoters of several genes including Xerico, which upregulates the abscisic acid pathway which is antagonistic to GA. DELLAs also promote transcription of the GA receptor, GIBBERELLIN INSENSITIVE DWARF 1 (GID1) and indirectly regulate GA biosynthesis genes enhancing GA responsiveness and feedback control. A structural analysis of GID1 provides a model for understanding GA signaling. GA binds within a pocket of GID1, changes GID1 conformation and increases the affinity of GID1 for DELLA proteins. GA/GID1/DELLA has increased affinity for an F-Box protein and DELLAs are subsequently degraded via the proteasome. Therefore, GA induces growth through degradation of the DELLAs. The binding of DELLA proteins to three of the PHYTOCHROME INTERACTING FACTOR (PIF) proteins integrates light and GA signaling pathways. This binding prevents PIFs 3, 4, and 5 from functioning as positive transcriptional regulators of growth in the dark. Since PIFs are degraded in light, these PIFs can only function in the combined absence of light and presence of GA. New analyses suggest that GA signaling evolved at the same time or just after the plant vascular system and before plants acquired the capacity for seed reproduction. An analysis of sequences cloned from Physcomitrella suggests that GID1 and DELLAs were the first to evolve but did not initially interact. The more recently diverging spike moss Selaginella has all the genes required for GA biosynthesis and signaling, but the role of GA response in Selaginella physiology remains a mystery.

  4. Downregulation of leptin inhibits growth and induces apoptosis of lung cancer cells via the Notch and JAK/STAT3 signaling pathways

    Directory of Open Access Journals (Sweden)

    Xian-Jie Zheng

    2016-06-01

    Full Text Available Previous studies have documented that leptin is involved in the pathogenesis of many human cancer types by regulation of numerous signal transduction pathways. The aim of this study was to investigate the biological roles of leptin and the mechanisms attributed to its action in non-small cell lung cancer (NSCLC cell lines. The expression of leptin was measured by quantitative real-time PCR and western blot in seven NSCLC cell lines. Proliferation and apoptosis of NSCLC cells in response to leptin knockdown were determined by MTT assay and flow cytometry, respectively. The effect of leptin knockdown on the Notch and JAK/STAT3 signaling pathways was further examined by western blot. Leptin expression was significantly increased in NSCLC cell lines compared with normal human bronchial epithelial cell HBE. Leptin knockdown inhibited cell proliferation and induced apoptosis in NSCLC cell lines through inactivation of the Notch and JAK/STAT3 signaling pathways. Furthermore, gene silencing of Notch signaling with Notch-1 siRNA or inhibition of JAK/STAT3 signaling by JSI-124, an inhibitor of STAT3, resulted in proliferation inhibition and apoptosis induction in NSCLC A549 cells. Our findings suggested that leptin knockdown could become a new approach for the prevention of lung cancer progression, which is likely to be mediated at least partially by inactivation of the Notch and JAK/STAT3 signaling pathways.

  5. Epidermal growth factor promotes proliferation of dermal papilla cells via Notch signaling pathway.

    Science.gov (United States)

    Zhang, Haihua; Nan, Weixiao; Wang, Shiyong; Zhang, Tietao; Si, Huazhe; Wang, Datao; Yang, Fuhe; Li, Guangyu

    2016-08-01

    The effect of epidermal growth factor (EGF) on the development and growth of hair follicle is controversial. In the present study, 2-20 ng/ml EGF promoted the growth of mink hair follicles in vitro, whereas 200 ng/ml EGF inhibited follicle growth. Further, dermal papilla (DP) cells, a group of mesenchymal cells that govern hair follicle development and growth, were isolated and cultured in vitro. Treatment with or forced expression of EGF accelerated proliferation and induced G1/S transition in DP cells. Moreover, EGF upregulated the expression of DP mesenchymal genes, such as alkaline phosphatase (ALP) and insulin-like growth factor (IGF-1), as well as the Notch pathway molecules including Notch1, Jagged1, Hes1 and Hes5. In addition, inhibition of Notch signaling pathway by DAPT significantly reduced the basal and EGF-enhanced proliferation rate, and also suppressed cell cycle progression. We also show that the expression of several follicle-regulatory genes, such as Survivin and Msx2, were upregulated by EGF, and was inhibited by DAPT. In summary, our study demonstrates that the concentration of EGF is critical for the switch between hair follicle growth and inhibition, and EGF promotes DP cell proliferation via Notch signaling pathway. Copyright © 2016 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM). All rights reserved.

  6. Õunpuu Karlovy Varys edukas

    Index Scriptorium Estoniae

    2010-01-01

    45. Karlovy Vary filmifestivali võistlusprogrammis "East of the West" märgiti ära Veiko Õunpuu film "Püha Tõnu kiusamine". Peaauhind läks rumeenlase Cristi Puiu filmile "Aurora". Grand prix´sai Augustĺ Vila film "La mosquitera". Teisi preemiasaajaid

  7. RETRACTED ARTICLE: Gradually varied flow computation in ...

    Indian Academy of Sciences (India)

    Mohammad Jahandar Malekabadi

    The article ''Gradually varied flow computation in channel networks by adaptive algorithm'' (DOI 10.1007/s12046- · 017-0640-x) which has been published online has been retracted by Chief Editor of the journal Sadhana as per the. Committee on Publication Ethics (COPE) guidelines on redundant publication.

  8. Ellipsometry with randomly varying polarization states

    NARCIS (Netherlands)

    Liu, Fenz; Lee, Christopher James; Chen, Juequan; Chen, J.; Louis, Eric; van der Slot, Petrus J.M.; Boller, Klaus J.; Bijkerk, Frederik

    2012-01-01

    We show that, under the right conditions, one can make highly accurate polarization-based measurements without knowing the absolute polarization state of the probing light field. It is shown that light, passed through a randomly varying birefringent material has a well-defined orbit on the Poincar

  9. Ellipsometry with random varying polarization state

    NARCIS (Netherlands)

    Liu, Fenz; van Albada, B.; Lee, c; Bijkerk, Frederik

    2012-01-01

    We show that, under the right conditions, one can make highly accurate polarization-based measurements without knowing the absolute polarization state of the probing light field. It is shown that light, passed through a randomly varying birefringent material has a well-defined orbit on the Poincar

  10. "Mina olin siin" esilinastub Karlovy Varys

    Index Scriptorium Estoniae

    2008-01-01

    Karlovy Vary filmifestivalil esilinastub Rene Vilbre noortefilm "Mina olin siin", mille aluseks on Sass Henno romaan "Mina olin siin. Esimene arest", stsenaariumi kirjutas Ilmar Raag. Film võistleb võistlusprogrammis "East of the West". Esitlema sõidavad R. Vilbre, R. Sildos, R. Kaljujärv, T. Tuisk

  11. Efficient Estimation in Heteroscedastic Varying Coefficient Models

    Directory of Open Access Journals (Sweden)

    Chuanhua Wei

    2015-07-01

    Full Text Available This paper considers statistical inference for the heteroscedastic varying coefficient model. We propose an efficient estimator for coefficient functions that is more efficient than the conventional local-linear estimator. We establish asymptotic normality for the proposed estimator and conduct some simulation to illustrate the performance of the proposed method.

  12. Filmihullu eluvesi voolab Karlovy Varys / Margit Tõnson

    Index Scriptorium Estoniae

    Tõnson, Margit, 1978-

    2010-01-01

    Karlovy Vary rahvusvahelisest filmifestivalist. Filmidest "Mr. Nobody" (rež. Jaco Van Dormaeli), "Kasside ema Teresa" (rež. Pawel Sala) ja "The Arbor" (rež. Clio Barnardi). Nimekiri võitnud töödest ja viimastel aastatel festivalil näidatud Eesti mängufilmidest

  13. Signaling cascades

    DEFF Research Database (Denmark)

    Feliu, Elisenda; Knudsen, Michael; Wiuf, Carsten

    2012-01-01

    for how the steady state concentrations and the total amounts of substrates, kinase, and phosphatates depend on each other. In particular, we use these to study how the responses (the activated substrates) vary as a function of the available amounts of substrates, kinase, and phosphatases. Our results...

  14. Components in time-varying graphs

    Science.gov (United States)

    Nicosia, Vincenzo; Tang, John; Musolesi, Mirco; Russo, Giovanni; Mascolo, Cecilia; Latora, Vito

    2012-06-01

    Real complex systems are inherently time-varying. Thanks to new communication systems and novel technologies, today it is possible to produce and analyze social and biological networks with detailed information on the time of occurrence and duration of each link. However, standard graph metrics introduced so far in complex network theory are mainly suited for static graphs, i.e., graphs in which the links do not change over time, or graphs built from time-varying systems by aggregating all the links as if they were concurrent in time. In this paper, we extend the notion of connectedness, and the definitions of node and graph components, to the case of time-varying graphs, which are represented as time-ordered sequences of graphs defined over a fixed set of nodes. We show that the problem of finding strongly connected components in a time-varying graph can be mapped into the problem of discovering the maximal-cliques in an opportunely constructed static graph, which we name the affine graph. It is, therefore, an NP-complete problem. As a practical example, we have performed a temporal component analysis of time-varying graphs constructed from three data sets of human interactions. The results show that taking time into account in the definition of graph components allows to capture important features of real systems. In particular, we observe a large variability in the size of node temporal in- and out-components. This is due to intrinsic fluctuations in the activity patterns of individuals, which cannot be detected by static graph analysis.

  15. Optical parametric amplification beyond the slowly varying ...

    Indian Academy of Sciences (India)

    −ω1 with amplitude A2. The pump wave is usually assumed to be so strong, i.e. is undepleted by the nonlinear interactions. In plane-wave approximation the equation for the pump, signal, and idler waves propagating along the z-axis with wave ...

  16. Detection of dynamically varying interaural time differences

    DEFF Research Database (Denmark)

    Kohlrausch, Armin; Le Goff, Nicolas; Breebaart, Jeroen

    2010-01-01

    Humans are highly sensitive to Interaural Time Differences (ITDs) in stimuli presented via headphones. For broadband noise stimuli of long durations, ITD detection thresholds can be as low as 10 to 15 ms. When the stimulus duration is shortened, thresholds increase by about a factor 2 for a tenfold...... to predict with a purely signal-driven model of perception and thus form an interesting challenge for modeling human localization....

  17. Anistropically varying conductivity in irreversible electroporation simulations.

    Science.gov (United States)

    Labarbera, Nicholas; Drapaca, Corina

    2017-11-01

    One recent area of cancer research is irreversible electroporation (IRE). Irreversible electroporation is a minimally invasive procedure where needle electrodes are inserted into the body to ablate tumor cells with electricity. The aim of this paper is to propose a mathematical model that incorporates a tissue's conductivity increasing more in the direction of the electrical field as this has been shown to occur in experiments. It was necessary to mathematically derive a valid form of the conductivity tensor such that it is dependent on the electrical field direction and can be easily implemented into numerical software. The derivation of a conductivity tensor that can take arbitrary functions for the conductivity in the directions tangent and normal to the electrical field is the main contribution of this paper. Numerical simulations were performed for isotropic-varying and anisotropic-varying conductivities to evaluate the importance of including the electrical field's direction in the formulation for conductivity. By starting from previously published experimental results, this paper derived a general formulation for an anistropic-varying tensor for implementation into irreversible electroporation modeling software. The anistropic-varying tensor formulation allows the conductivity to take into consideration both electrical field direction and magnitude, as opposed to previous published works that only took into account electrical field magnitude. The anisotropic formulation predicts roughly a five percent decrease in ablation size for the monopolar simulation and approximately a ten percent decrease in ablation size for the bipolar simulations. This is a positive result as previously reported results found the isotropic formulation to overpredict ablation size for both monopolar and bipolar simulations. Furthermore, it was also reported that the isotropic formulation overpredicts the ablation size more for the bipolar case than the monopolar case. Thus, our

  18. [Role of Notch-Jagged/Delta signaling pathway in arthritis rats of reduced lung function induced by adjuvant].

    Science.gov (United States)

    Wan, Lei; Liu, Jian; Huang, Chuanbing; Wang, Yuan; Zhang, Xiaojun; Ruan, Liping; Wang, Yali; Ye, Wenfang

    2014-02-01

    To observe the changes of pulmonary function and Notch signaling pathway of lung tissues in adjuvant-induced arthritis rats, and to investigate the mechanism of reduced lung function. A total of 30 rats were randomly divided into a normal group and a model group. Rats in the model group were induced to establish the adjuvant arthritis AA model by intradermally injecting 0.1 mL Freund's complete adjuvant into the right paw. After 30 days, we observed the paw edema volume, arthritis index, pulmonary function, histomorphology, and Notch receptor/ligand of the lung tissue. Compared with the normal group, the paw edema volume, arthritis index, average expiratory flow within 0.3 s (FEV0.3/FVC), and the level of Notch3, Notch4 and Jagged2 of the lung tissue in the model group was significantly increased, while maximum expiratory flow at 50% of vital capacity (FEF50), maximum expiratory flow at 75% of vital capacity (FEF75), forced expiratory flow (PEF) and the expression of Notch1 of Jagged1 and Delta1 in the lung were significantly decreased (Pfunction declines and significantly correlates with the expression of Notch receptor/ligand. The deposition of immune complex in the lung after the injection of CFA activates the Notch signaling pathway, and results in further decline of pulmonary function by signaling cascades.

  19. Controlling Electricity Consumption by Forecasting its Response to Varying Prices

    DEFF Research Database (Denmark)

    Corradi, Olivier; Ochsenfeld, Henning Peter; Madsen, Henrik

    2013-01-01

    In a real-time electricity pricing context where consumers are sensitive to varying prices, having the ability to anticipate their response to a price change is valuable. This paper proposes models for the dynamics of such price-response, and shows how these dynamics can be used to control...... electricity consumption using a one-way price signal. Estimation of the price-response is based on data measurable at grid level, removing the need to install sensors and communication devices between each individual consumer and the price-generating entity. An application for price-responsive heating systems...... is studied based on real data, before conducting a control by price experiment using a mixture of real and synthetic data. With the control objective of following a constant consumption reference, peak heating consumption is reduced by nearly 5%, and 11% of the mean daily heating consumption is shifted....

  20. A Diagnostic System for Speed-Varying Motor Rotary Faults

    Directory of Open Access Journals (Sweden)

    Chwan-Lu Tseng

    2014-01-01

    Full Text Available This study proposed an intelligent rotary fault diagnostic system for motors. A sensorless rotational speed detection method and an improved dynamic structural neural network are used. Moreover, to increase the convergence speed of training, a terminal attractor method and a hybrid discriminant analysis are also adopted. The proposed method can be employed to detect the rotary frequencies of motors with varying speeds and can enhance the discrimination of motor faults. To conduct the experiments, this study used wireless sensor nodes to transmit vibration data and employed MATLAB to write codes for functional modules, including the signal processing, sensorless rotational speed estimation, neural network, and stochastic process control chart. Additionally, Visual Basic software was used to create an integrated human-machine interface. The experimental results regarding the test of equipment faults indicated that the proposed novel diagnostic system can effectively estimate rotational speeds and provide superior ability of motor fault discrimination with fast training convergence.

  1. Probabilistic Recovery Guarantees for Sparsely Corrupted Signals

    CERN Document Server

    Pope, Graeme; Studer, Christoph

    2012-01-01

    We consider the recovery of sparse signals subject to sparse interference, as introduced in Studer et al., IEEE Trans. IT, 2012. We present novel probabilistic recovery guarantees for this framework, covering varying degrees of knowledge of the signal and interference support, which are relevant for a large number of practical applications. Our results assume that the sparsifying dictionaries are solely characterized by coherence parameters and we require randomness only in the signal and/or interference. The obtained recovery guarantees show that one can recover sparsely corrupted signals with overwhelming probability, even if the sparsity of both the signal and interference scale (near) linearly with the number of measurements.

  2. A time-varying magnetic flux concentrator

    Science.gov (United States)

    Kibret, B.; Premaratne, M.; Lewis, P. M.; Thomson, R.; Fitzgerald, P. B.

    2016-08-01

    It is known that diverse technological applications require the use of focused magnetic fields. This has driven the quest for controlling the magnetic field. Recently, the principles in transformation optics and metamaterials have allowed the realization of practical static magnetic flux concentrators. Extending such progress, here, we propose a time-varying magnetic flux concentrator cylindrical shell that uses electric conductors and ferromagnetic materials to guide magnetic flux to its center. Its performance is discussed based on finite-element simulation results. Our proposed design has potential applications in magnetic sensors, medical devices, wireless power transfer, and near-field wireless communications.

  3. Conceptual Modeling of Time-Varying Information

    DEFF Research Database (Denmark)

    Gregersen, Heidi; Jensen, Christian Søndergaard

    2004-01-01

    A wide range of database applications manage information that varies over time. Many of the underlying database schemas of these were designed using the Entity-Relationship (ER) model. In the research community as well as in industry, it is common knowledge that the temporal aspects of the mini-world...... are important, but difficult to capture using the ER model. Several enhancements to the ER model have been proposed in an attempt to support the modeling of temporal aspects of information. Common to the existing temporally extended ER models, few or no specific requirements to the models were given...

  4. Linear Parameter Varying Control of Induction Motors

    DEFF Research Database (Denmark)

    Trangbæk, Klaus

    The subject of this thesis is the development of linear parameter varying (LPV) controllers and observers for control of induction motors. The induction motor is one of the most common machines in industrial applications. Being a highly nonlinear system, it poses challenging control problems...... for high performance applications. This thesis demonstrates how LPV control theory provides a systematic way to achieve good performance for these problems. The main contributions of this thesis are the application of the LPV control theory to induction motor control as well as various contributions...

  5. Time varying behaviour of the loudspeaker suspension

    DEFF Research Database (Denmark)

    Agerkvist, Finn; Pedersen, Bo Rohde

    2009-01-01

    The compliance of the loudspeaker suspension is known to depend on the recent excitation level history. Previous investigations have shown that the electrical power as well as displacement and velocity plays a role. In this paper the hypothesis that the changes in compliance are caused mainly...... by how much the suspension has been stretched, i.e., the maximum displacement, is investigated. For this purpose the changes in compliance are measured when exposing the loudspeaker to different levels and types of electrical excitation signals, as well as mechanical excitation only. For sinusoidal...

  6. Live Convolution with Time-Varying Filters

    Directory of Open Access Journals (Sweden)

    Øyvind Brandtsegg

    2018-01-01

    Full Text Available The paper presents two new approaches to artefact-free real-time updates of the impulse response in convolution. Both approaches are based on incremental updates of the filter. This can be useful for several applications within digital audio processing: parametrisation of convolution reverbs, dynamic filters, and live convolution. The development of these techniques has been done within the framework of a research project on crossadaptive audio processing methods for live performance. Our main motivation has thus been live convolution, where the signals from two music performers are convolved with each other, allowing the musicians to “play through each other’s sound”.

  7. Prosocial Signalling

    DEFF Research Database (Denmark)

    Kahsay, Goytom Abraha

    In contrast to the standard economic theory predictions, it seems clear that people do spend their time and resource to benefit others. Many lab and field experiment studies show that people display prosocial preferences such as altruism, reciprocity and conditional cooperation, fairness, etc...... signalling can cause reverse price reactions resembling the crowding-out of pre-existing motives for prosocial behavior seen in situations of volunteering and charitable giving. Using a unique combination of questionnaire and purchase panel data, it presents evidence of such reputation-driven reverse price...

  8. Stereoscopic depth perception varies with hues

    Science.gov (United States)

    Chen, Zaiqing; Shi, Junsheng; Tai, Yonghang; Yun, Lijun

    2012-09-01

    The contribution of color information to stereopsis is controversial, and whether the stereoscopic depth perception varies with chromaticity is ambiguous. This study examined the changes in depth perception caused by hue variations. Based on the fact that a greater disparity range indicates more efficient stereoscopic perception, the effect of hue variations on depth perception was evaluated through the disparity range with random-dot stereogram stimuli. The disparity range was obtained by constant-stimulus method for eight chromaticity points sampled from the CIE 1931 chromaticity diagram. Eight sample points include four main color hues: red, yellow, green, and blue at two levels of chroma. The results show that the disparity range for the yellow hue is greater than the red hue, the latter being greater than the blue hue and the disparity range for green hue is smallest. We conclude that the perceived depth is not the same for different hues for a given size of disparity. We suggest that the stereoscopic depth perception can vary with chromaticity.

  9. Optimizing power output by varying repetition tempo.

    Science.gov (United States)

    Pryor, Riana R; Sforzo, Gary A; King, Deborah L

    2011-11-01

    The effects of varying interrepetition rest and eccentric velocity on power output (PO) and the number of repetitions performed during a bench press set were examined in 24 college-aged resistance trained men. On 6 separate occasions, subjects performed a set of bench press at 80% 1 repetition maximum until volitional fatigue. For each of the 6 repetition tempo trials, the bench press set was paced by metronome to a unique repetition tempo involving a combination of the following: interrepetition rest of 0 or 4 seconds; eccentric velocity of 1 or 4 seconds and bottom rest of 0 or 3 seconds. The velocity of concentric contraction was maximal during all 6 tempo trials. During each trial, video data were captured to determine PO variables and number of successful repetitions completed at each tempo. One-way repeated measures analysis of variance showed tempos with a fast eccentric phase (1 second), and no bottom rest produced significantly greater (p ≤ 0.05) PO and repetitions than tempos involving slower eccentric velocity (4 seconds) or greater bottom rest (4 seconds). This combination of greater repetitions and PO resulted in a greater volume of work. Varying interrepetition rest (1 or 4 seconds) did not significantly affect PO or repetitions. The results of this study support the use of fast eccentric speed and no bottom rest during acute performance testing to maximize PO and number of repetitions during a set of bench press.

  10. Adaptive time-varying detrended fluctuation analysis.

    Science.gov (United States)

    Berthouze, Luc; Farmer, Simon F

    2012-07-30

    Detrended fluctuation analysis (DFA) is a technique commonly used to assess and quantify the presence of long-range temporal correlations (LRTCs) in neurophysiological time series. Convergence of the method is asymptotic only and therefore its application assumes a constant scaling exponent. However, most neurophysiological data are likely to involve either spontaneous or experimentally induced scaling exponent changes. We present a novel extension of the DFA method that permits the characterisation of time-varying scaling exponents. The effectiveness of the methodology in recovering known changes in scaling exponents is demonstrated through its application to synthetic data. The dependence of the method on its free parameters is systematically explored. Finally, application of the methodology to neurophysiological data demonstrates that it provides experimenters with a way to identify previously un-recognised changes in the scaling exponent in the data. We suggest that this methodology will make it possible to go beyond a simple demonstration of the presence of scaling to an appreciation of how it may vary in response to either intrinsic changes or experimental perturbations. Copyright © 2012 Elsevier B.V. All rights reserved.

  11. An integrative time-varying frequency detection and channel sounding method for dynamic plasma sheath

    Science.gov (United States)

    Shi, Lei; Yao, Bo; Zhao, Lei; Liu, Xiaotong; Yang, Min; Liu, Yanming

    2018-01-01

    The plasma sheath-surrounded hypersonic vehicle is a dynamic and time-varying medium and it is almost impossible to calculate time-varying physical parameters directly. The in-fight detection of the time-varying degree is important to understand the dynamic nature of the physical parameters and their effect on re-entry communication. In this paper, a constant envelope zero autocorrelation (CAZAC) sequence based on time-varying frequency detection and channel sounding method is proposed to detect the plasma sheath electronic density time-varying property and wireless channel characteristic. The proposed method utilizes the CAZAC sequence, which has excellent autocorrelation and spread gain characteristics, to realize dynamic time-varying detection/channel sounding under low signal-to-noise ratio in the plasma sheath environment. Theoretical simulation under a typical time-varying radio channel shows that the proposed method is capable of detecting time-variation frequency up to 200 kHz and can trace the channel amplitude and phase in the time domain well under -10 dB. Experimental results conducted in the RF modulation discharge plasma device verified the time variation detection ability in practical dynamic plasma sheath. Meanwhile, nonlinear phenomenon of dynamic plasma sheath on communication signal is observed thorough channel sounding result.

  12. TDR Using Autocorrelation and Varying-Duration Pulses

    Science.gov (United States)

    Lucena, Angel; Mullinex, Pam; Huang, PoTien; Santiago, Josephine; Mata, Carlos; Zavala, Carlos; Lane, John

    2008-01-01

    In an alternative to a prior technique of time-domain-reflectometry (TDR) in which very short excitation pulses are used, the pulses have very short rise and fall times and the pulse duration is varied continuously between a minimum and a maximum value. In both the present and prior techniques, the basic idea is to (1) measure the times between the generation of excitation pulses and the reception of reflections of the pulses as indications of the locations of one or more defects along a cable and (2) measure the amplitudes of the reflections as indication of the magnitudes of the defects. In general, an excitation pulse has a duration T. Each leading and trailing edge of an excitation pulse generates a reflection from a defect, so that a unique pair of reflections is associated with each defect. In the present alternative technique, the processing of the measured reflection signal includes computation of the autocorrelation function R(tau) identical with fx(t)x(t-tau)dt where t is time, x(t) is the measured reflection signal at time t, and taus is the correlation interval. The integration is performed over a measurement time interval short enough to enable identification and location of a defect within the corresponding spatial interval along the cable. Typically, where there is a defect, R(tau) exhibits a negative peak having maximum magnitude for tau in the vicinity of T. This peak can be used as a means of identifying a leading-edge/trailing-edge reflection pair. For a given spatial interval, measurements are made and R(tau) computed, as described above, for pulse durations T ranging from the minimum to the maximum value. The advantage of doing this is that the effective signal-to-noise ratio may be significantly increased over that attainable by use of a fixed pulse duration T.

  13. Notch Signaling Is Associated With ALDH Activity And An Aggressive Metastatic Phenotype In Murine Osteosarcoma Cells

    Directory of Open Access Journals (Sweden)

    Xiaodong eMu

    2013-06-01

    Full Text Available Osteosarcoma (OS is the most common primary malignancy of bone, and pulmonary metastatic disease accounts for nearly all mortality. However, little is known about the biochemical signaling alterations that drive the progression of metastatic disease. Two murine OS cell populations, K7M2 and K12, are clonally related but differ significantly in their metastatic phenotypes and therefore represent excellent tools for studying metastatic OS molecular biology. K7M2 cells are highly metastatic, whereas K12 cells display limited metastatic potential. Here we report that the expression of Notch genes (Notch1, 2, 4 are up-regulated, including downstream targets Hes1 and Stat3, in the highly metastatic K7M2 cells compared to the less metastatic K12 cells, indicating that the Notch signaling pathway is more active in K7M2 cells. We have previously described that K7M2 cells exhibit higher levels of aldehyde dehydrogenase (ALDH activity. Here we report that K7M2 cell ALDH activity is reduced with Notch inhibition, suggesting that ALDH activity may be regulated in part by the Notch pathway. Notch signaling is also associated with increased resistance to oxidative stress, migration, invasion, and VEGF expression in vitro. However, Notch inhibition did not significantly alter K7M2 cell proliferation. In conclusion, we provide evidence that Notch signaling is associated with ALDH activity and increased metastatic behavior in OS cells. Both Notch and ALDH are putative molecular targets for the treatment and prevention of OS metastasis.

  14. Huang Qi Decoction Prevents BDL-Induced Liver Fibrosis Through Inhibition of Notch Signaling Activation.

    Science.gov (United States)

    Zhang, Xiao; Xu, Ying; Chen, Jia-Mei; Liu, Cheng; Du, Guang-Li; Zhang, Hua; Chen, Gao-Feng; Jiang, Shi-Li; Liu, Cheng-Hai; Mu, Yong-Ping; Liu, Ping

    2017-01-01

    Notch signaling has been demonstrated to be involved in ductular reactions and fibrosis. Previous studies have shown that Huang Qi Decoction (HQD) can prevent the progression of cholestatic liver fibrosis (CLF). However, whether HQD affects the Notch signaling pathway is unclear. In this study, CLF was established by common bile duct ligation (BDL) in rats. At the end of the first week, the rats were randomly divided into a model group (i.e., BDL), an HQD group, and a sorafenib positive control group (SORA) and were treated for 3 weeks. Bile duct proliferation and liver fibrosis were determined by tissue staining. Activation of the Notch signaling pathway was evaluated by analyzing expressions of Notch-1, -2, -3, and -4, Jagged (JAG) 1, and Delta like (DLL)-1, -3, and -4. The results showed that HQD significantly reduced the deposition of collagen and the Hyp content of liver tissue and inhibited the activation of HSCs compared with the BDL group. In addition, HQD significantly decreased the protein and mRNA expressions of TGF-[Formula: see text]1 and [Formula: see text]-SMA. In contrast, HQD significantly enhanced expression of the Smad 7 protein. HQD also reduced biliary epithelial cell proliferation, and reduced the mRNA levels of CK7, CK8, CK18, SRY-related high mobility group-box gene (SOX) 9, epithelial cell adhesion molecule (EpCAM) and the positive areas of CK19 and OV6. In addition, the mRNA and protein expressions of Notch-3, -4, JAG1, and DLL-1, -3 were significantly reduced in the HQD compared to the BDL group. These results demonstrated that HQD may prevent biliary liver fibrosis through inhibition of the Notch signaling pathway, and it may be a potential treatment for cholestatic liver disease.

  15. Climate dynamics: Why does climate vary?

    Science.gov (United States)

    Schultz, Colin

    2011-08-01

    In recent years, climate change has become a major focus of public and political discussion. Ongoing scientific inquiry, revolving predominantly around understanding the anthropogenic effects of rising greenhouse gas levels, coupled with how successfully findings are communicated to the public, has made climate science both contentious and exigent. In the AGU monograph Climate Dynamics: Why Does Climate Vary?, editors De-Zheng Sun and Frank Bryan reinforce the importance of investigating the complex dynamics that underlie the natural variability of the climate system. Understanding this complexity—particularly how the natural variability of climate may enhance or mask anthropogenic warming—could have important consequences for the future. In this interview, Eos talks to De-Zheng Sun.

  16. Time varying arctic climate change amplification

    Energy Technology Data Exchange (ETDEWEB)

    Chylek, Petr [Los Alamos National Laboratory; Dubey, Manvendra K [Los Alamos National Laboratory; Lesins, Glen [DALLHOUSIE U; Wang, Muyin [NOAA/JISAO

    2009-01-01

    During the past 130 years the global mean surface air temperature has risen by about 0.75 K. Due to feedbacks -- including the snow/ice albedo feedback -- the warming in the Arctic is expected to proceed at a faster rate than the global average. Climate model simulations suggest that this Arctic amplification produces warming that is two to three times larger than the global mean. Understanding the Arctic amplification is essential for projections of future Arctic climate including sea ice extent and melting of the Greenland ice sheet. We use the temperature records from the Arctic stations to show that (a) the Arctic amplification is larger at latitudes above 700 N compared to those within 64-70oN belt, and that, surprisingly; (b) the ratio of the Arctic to global rate of temperature change is not constant but varies on the decadal timescale. This time dependence will affect future projections of climate changes in the Arctic.

  17. Time-Varying Periodicity in Intraday Volatility

    DEFF Research Database (Denmark)

    Andersen, Torben Gustav; Thyrsgaard, Martin; Todorov, Viktor

    with a constant time-of-day periodic component. We first construct time-of-day volatility estimates and studentize the high-frequency returns with these periodic components. If the intraday volatility periodicity is invariant over time, then the distribution of the studentized returns should be identical across......We develop a nonparametric test for deciding whether return volatility exhibits time-varying intraday periodicity using a long time-series of high-frequency data. Our null hypothesis, commonly adopted in work on volatility modeling, is that volatility follows a stationary process combined...... the trading day. Consequently, the test is based on comparing the empirical characteristic function of the studentized returns across the trading day. The limit distribution of the test depends on the error in recovering volatility from discrete return data and the empirical process error associated...

  18. Optical vortex array in spatially varying lattice

    CERN Document Server

    Kapoor, Amit; Senthilkumaran, P; Joseph, Joby

    2015-01-01

    We present an experimental method based on a modified multiple beam interference approach to generate an optical vortex array arranged in a spatially varying lattice. This method involves two steps which are: numerical synthesis of a consistent phase mask by using two-dimensional integrated phase gradient calculations and experimental implementation of produced phase mask by utilizing a phase only spatial light modulator in an optical 4f Fourier filtering setup. This method enables an independent variation of the orientation and period of the vortex lattice. As working examples, we provide the experimental demonstration of various spatially variant optical vortex lattices. We further confirm the existence of optical vortices by formation of fork fringes. Such lattices may find applications in size dependent trapping, sorting, manipulation and photonic crystals.

  19. Supernumerary teeth vary depending on gender

    Directory of Open Access Journals (Sweden)

    Erika Calvano Küchler

    2011-02-01

    Full Text Available The presence of supernumerary teeth (ST is a dental developmental anomaly of patterning and morphogenesis. Its variability of morphology, location and developmental timing can shed light on its etiology. In this work we report ST patterns. Orthopantomograms of 1,166 pediatric subjects were examined and the morphology, location and timing of the formation of ST were determined. The frequency of supernumerary teeth in the studied population was 2.3% (n = 27. Twenty-five subjects presented one ST. Maxilla midline was the most commonly affected region (nine cases. We noted high incidence of conical morphology in the midline region. Only teeth with tuberculate morphology presented delayed formation. ST in the midline region occurred more often in males whereas ST in the incisor region were more common in females. In conclusion, ST patterns vary depending on gender.

  20. Niacin Inhibits Vascular Inflammation via Downregulating Nuclear Transcription Factor-κB Signaling Pathway

    Science.gov (United States)

    Si, Yanhong; Zhang, Ying; Zhao, Jilong; Guo, Shoudong; Zhai, Lei; Yao, Shutong; Sang, Hui; Yang, Nana; Song, Guohua; Gu, Jue; Qin, Shucun

    2014-01-01

    The study aimed to investigate the effect of niacin on vascular inflammatory lesions in vivo and in vitro as well as its lipid-regulating mechanism. In vivo study revealed that niacin downregulated the levels of inflammatory factors (IL-6 and TNF-α) in plasma, suppressed protein expression of CD68 and NF-κB p65 in arterial wall, and attenuated oxidative stress in guinea pigs that have been fed high fat diet. In vitro study further confirmed that niacin decreased the secretion of IL-6 and TNF-α and inhibited NF-κB p65 and notch1 protein expression in oxLDL-stimulated HUVECs and THP-1 macrophages. Moreover, niacin attenuated oxLDL-induced apoptosis of HUVECs as well. In addition, niacin significantly lessened lipid deposition in arterial wall, increased HDL-C and apoA levels and decreased TG and non-HDL-C levels in plasma, and upregulated the mRNA amount of cholesterol 7α-hydroxylase A1 in liver of guinea pigs. These data suggest for the first time that niacin inhibits vascular inflammation in vivo and in vitro via downregulating NF-κB signaling pathway. Furthermore, niacin also modulates plasma lipid by upregulating the expression of factors involved in the process of reverse cholesterol transport. PMID:24991087

  1. Notch signaling in the epididymal epithelium regulates sperm motility and is transferred at a distance within epididymosomes.

    Science.gov (United States)

    Murta, D; Batista, M; Silva, E; Trindade, A; Henrique, D; Duarte, A; Lopes-da-Costa, L

    2016-03-01

    Spermatozoa undergo sequential maturation changes during their transit along the epididymis. These changes are modulated by the epididymal epithelium and require a finely tuned gene expression. The Notch cell signaling pathway is a major regulator of cell fate decisions in several tissues, including the testis. Here, we evaluated the transcription and expression patterns of Notch components (Notch1-3, Dll1, Dll4, and Jagged1) and effectors (Hes1-2 and Hes5) in the adult mouse epididymis, and evaluated the role of Notch signaling in the epididymis through its in vivo blockade following administration of an inhibitor (DAPT). Notch components and effectors were dynamically transcribed and expressed in the epididymis and vas deferens, each segment exhibiting a specific combination of epithelial receptor/ligand/effector expression patterns. Nuclear detection of Notch effectors indicates that Notch signaling was active. Notch components (but not effectors) were identified in the cytoplasmic droplet of spermatozoa, in a dynamic and specific pattern along the epididymis. In addition, Notch components were identified within large and small vesicles in the epididymal lumen. A purified population of these membranous vesicles from different epididymal segments was obtained, and through dot blot analysis, it was confirmed that Notch components were carried within these vesicles in a dynamic pattern along the epididymal lumen. We hypothesize that these vesicles (epididymosomes) allow Notch signaling at distance from epididymal epithelial cells to spermatozoa. DAPT-induced in vivo Notch signaling blockade, although showing a low efficiency, disrupted the expression patterns of Notch components and effectors in the epididymal epithelium and in spermatozoa, and significantly decreased sperm motility, although not affecting male fertility. These results prompt for a regulatory role of Notch signaling in epididymal epithelial function and sperm maturation. © 2016 American Society of

  2. Varied acceptance of clinical trial results.

    Science.gov (United States)

    Klimt, C R

    1989-12-01

    The subject of varied acceptance of clinical trial results is discussed in the context of review of trials with which I have been involved and my subjective evaluation of their impact on the practice of clinical medicine. My experience goes back to 1949 and a World Health Organization trial of hyperimmune gamma globulin against rabies. This was followed by a large trial of secondary prevention of poliomyelitis. I participated in the planning and initiation of the first chronic disease trial, the University Group Diabetes Program (UGDP). The latter lasted for 15 years and its ramifications continue to this day. My next trial was the Coronary Drug Project (CDP), a complex trial with more than 8,000 patients. The trials of aspirin and aspirin combined with persantine (the CDPA, AMIS, PARIS I, and PARIS II) followed. My last three trials were a trial of photocoagulation in diabetic retinopathy (DRS), a six-country trial of the antiarrhythmic drug mexiletine (IMPACT), and a study involving two diagnostic procedures for pulmonary embolism (PIOPED). When one considers, in retrospect, the plethora of trials one is struck by the uniform absence of a priori considerations of the impact on medical practice, or likely lack thereof, of possible outcomes.

  3. Microsatellites in varied arenas of research

    Directory of Open Access Journals (Sweden)

    K S Remya

    2010-01-01

    Full Text Available Microsatellites known as simple-sequence repeats (SSRs or short-tandem repeats (STRs, represent specific sequences of DNA consisting of tandemly repeated units of one to six nucleotides. The repetitive nature of microsatellites makes them particularly prone to grow or shrink in length and these changes can have both good and bad consequences for the organisms that possess them. They are responsible for various neurological diseases and hence the same cause is now utilized for the early detection of various diseases, such as, Schizophrenia and Bipolar Disorder, Congenital generalized Hypertrichosis, Asthma, and Bronchial Hyperresponsiveness. These agents are widely used for forensic identification and relatedness testing, and are predominant genetic markers in this area of application. The application of microsatellites is an extending web and covers the varied scenarios of science, such as, conservation biology, plant genetics, and population studies. At present, researches are progressing round the globe to extend the use of these genetic repeaters to unmask the hidden genetic secrets behind the creation of the world.

  4. Dermatophyte susceptibility varies towards antimicrobial textiles.

    Science.gov (United States)

    Hammer, Timo R; Mucha, Helmut; Hoefer, Dirk

    2012-07-01

    Dermatophytoses are a widespread problem worldwide. Textiles in contact with infected skin can serve as a carrier for fungus propagation. Hitherto, it is unknown, whether antifungal textiles could contribute in controlling dermatophytes e.g. by disrupting the chain of infection. Testing of antimicrobial fabrics for their antifungal activities therefore is a fundamental prerequisite to assess the putative clinical relevance of textiles for dermatophyte prevention. Fabrics finished with either didecyldimethylammonium chloride (DDAC), poly-hexamethylenbiguanide, copper and two silver chloride concentrations were tested for their antifungal activity against Trichophyton rubrum, Trichophyton mentagrophytes and Candida albicans. To prove dermatophyte susceptibility towards the textiles, swatches were subjected to DIN EN 14199 (Trichophyton sp.) or DIN EN ISO 20743 (C. albicans) respectively. In addition, samples were embedded, and semi-thin sections were analysed microscopically. While all samples showed a clear inhibition of C. albicans, activity against Trichophyton sp. varied significantly: For example, DDAC completely inhibited T. rubrum growth, whereas T. mentagrophytes growth remained unaffected even in direct contact to the fibres. The results favour to add T. mentagrophytes as a test organism in textile dermatophyte efficacy tests. Microscopic analysis of swatches allowed detailed evaluation of additional parameters like mycelium thickness, density and hyphae penetration depth into the fabric. © 2011 Blackwell Verlag GmbH.

  5. Varying Inundation Regimes Differentially Affect Natural and ...

    Science.gov (United States)

    Climate change is altering sea-level rise rates and precipitation patterns worldwide. Coastal wetlands are vulnerable to these changes. System responses to stressors are important for resource managers and environmental stewards to understand in order to best manage them. Thin layer sand or sediment application to drowning and eroding marshes is one approach to build elevation and resilience. The above- and below-ground structure, soil carbon dioxide emissions, and pore water constituents in vegetated natural marsh sediments and sand-amended sediments were examined at varying inundation regimes between mean sea level and mean high water (0.82 m NAVD88 to 1.49 m NAVD88) in a field experiment at Laws Point, part of the Plum Island Sound Estuary (MA). Significantly lower salinities, pH, sulfides, phosphates, and ammonium were measured in the sand-amended sediments than in the natural sediments. In natural sediments there was a pattern of increasing salinity with increasing elevation while in the sand-amended sediments the trend was reversed, showing decreasing salinity with increasing elevation. Sulfide concentrations generally increased from low to high inundation with highest concentrations at the highest inundation (i.e., at the lowest elevations). High pore water phosphate concentrations were measured at low elevations in the natural sediments, but the sand-amended treatments had mostly low concentrations of phosphate and no consistent pattern with elevation. A

  6. Functional Piezocrystal Characterisation under Varying Conditions

    Directory of Open Access Journals (Sweden)

    Xiaochun Liao

    2015-12-01

    Full Text Available Piezocrystals, especially the relaxor-based ferroelectric crystals, have been subject to intense investigation and development within the past three decades, motivated by the performance advantages offered by their ultrahigh piezoelectric coefficients and higher electromechanical coupling coefficients than piezoceramics. Structural anisotropy of piezocrystals also provides opportunities for devices to operate in novel vibration modes, such as the d36 face shear mode, with domain engineering and special crystal cuts. These piezocrystal characteristics contribute to their potential usage in a wide range of low- and high-power ultrasound applications. In such applications, conventional piezoelectric materials are presently subject to varying mechanical stress/pressure, temperature and electric field conditions. However, as observed previously, piezocrystal properties are significantly affected by a single such condition or a combination of conditions. Laboratory characterisation of the piezocrystal properties under these conditions is therefore essential to fully understand these materials and to allow electroacoustic transducer design in realistic scenarios. This will help to establish the extent to which these high performance piezocrystals can replace conventional piezoceramics in demanding applications. However, such characterisation requires specific experimental arrangements, examples of which are reported here, along with relevant results. The measurements include high frequency-resolution impedance spectroscopy with the piezocrystal material under mechanical stress 0–60 MPa, temperature 20–200 °C, high electric AC drive and DC bias. A laser Doppler vibrometer and infrared thermal camera are also integrated into the measurement system for vibration mode shape scanning and thermal conditioning with high AC drive. Three generations of piezocrystal have been tested: (I binary, PMN-PT; (II ternary, PIN-PMN-PT; and (III doped ternary, Mn

  7. Toxoplasma gondii seroprevalence varies by cat breed.

    Science.gov (United States)

    Must, Kärt; Hytönen, Marjo K; Orro, Toomas; Lohi, Hannes; Jokelainen, Pikka

    2017-01-01

    Toxoplasma gondii is a widespread zoonotic parasite that is relevant for veterinary and public health. The domestic cat, the definitive host species with the largest worldwide population, has become evolutionarily and epidemiologically the most important host of T. gondii. The outcome of T. gondii infection is influenced by congenital and acquired host characteristics. We detected differences in T. gondii seroprevalence by cat breed in our previous studies. The aims of this study were to estimate T. gondii seroprevalence in selected domestic cat breeds, and to evaluate whether being of a certain breed is associated with T. gondii seropositivity, when the age and lifestyle of the cat are taken into account. The studied breeds were the Birman, British Shorthair, Burmese, Korat, Norwegian Forest Cat, Ocicat, Persian, and Siamese. Plasma samples were analyzed for the presence of immunoglobulin G antibodies against T. gondii with a commercial direct agglutination test at dilution 1:40. The samples were accompanied by owner-completed questionnaires that provided background data on the cats. Overall, 41.12% of the 1121 cats tested seropositive, and the seroprevalence increased with age. The Burmese had the lowest seroprevalence (18.82%) and the Persian had the highest (60.00%). According to the final multivariable logistic regression model, the odds to test seropositive were four to seven times higher in Birmans, Ocicats, Norwegian Forest Cats, and Persians when compared with the Burmese, while older age and receiving raw meat were also risk factors for T. gondii seropositivity. This study showed that T. gondii seroprevalence varies by cat breed and identified being of certain breeds, older age, and receiving raw meat as risk factors for seropositivity.

  8. Functional Piezocrystal Characterisation under Varying Conditions.

    Science.gov (United States)

    Liao, Xiaochun; Qiu, Zhen; Jiang, Tingyi; Sadiq, Muhammad R; Huang, Zhihong; Demore, Christine E M; Cochran, Sandy

    2015-12-02

    Piezocrystals, especially the relaxor-based ferroelectric crystals, have been subject to intense investigation and development within the past three decades, motivated by the performance advantages offered by their ultrahigh piezoelectric coefficients and higher electromechanical coupling coefficients than piezoceramics. Structural anisotropy of piezocrystals also provides opportunities for devices to operate in novel vibration modes, such as the d36 face shear mode, with domain engineering and special crystal cuts. These piezocrystal characteristics contribute to their potential usage in a wide range of low- and high-power ultrasound applications. In such applications, conventional piezoelectric materials are presently subject to varying mechanical stress/pressure, temperature and electric field conditions. However, as observed previously, piezocrystal properties are significantly affected by a single such condition or a combination of conditions. Laboratory characterisation of the piezocrystal properties under these conditions is therefore essential to fully understand these materials and to allow electroacoustic transducer design in realistic scenarios. This will help to establish the extent to which these high performance piezocrystals can replace conventional piezoceramics in demanding applications. However, such characterisation requires specific experimental arrangements, examples of which are reported here, along with relevant results. The measurements include high frequency-resolution impedance spectroscopy with the piezocrystal material under mechanical stress 0-60 MPa, temperature 20-200 °C, high electric AC drive and DC bias. A laser Doppler vibrometer and infrared thermal camera are also integrated into the measurement system for vibration mode shape scanning and thermal conditioning with high AC drive. Three generations of piezocrystal have been tested: (I) binary, PMN-PT; (II) ternary, PIN-PMN-PT; and (III) doped ternary, Mn:PIN-PMN-PT. Utilising

  9. Circular motion analysis of time-varying bioimpedance.

    Science.gov (United States)

    Sanchez, B; Louarroudi, E; Rutkove, S B; Pintelon, R

    2015-11-01

    This paper presents a step forward towards the analysis of a linear periodically time-varying (PTV) bioimpedance ZPTV(jw, t), which is an important subclass of a linear time-varying (LTV) bioimpedance. Similarly to the Fourier coefficients of a periodic signal, a PTV impedance can be decomposed into frequency dependent impedance phasors, [Formula: see text], that are rotating with an angular speed of wr = 2πr/TZ. The vector length of these impedance phasors corresponds to the amplitude of the rth-order harmonic impedance |Zr( jw)| and the initial phase is given by Φr(w, t0) = [Symbol: see text]Zr( jw) + 2πrt0/TZ, with t0∈[0, T] being a time instant within the measurement time T. The impedance period TZ stands for the cycle length of the bio-system under investigation; for example, the elapsed time between two consecutive R-waves in the electrocardiogram or the breathing periodicity in case of the heart or lungs, respectively. First, it is demonstrated that the harmonic impedance phasor [Formula: see text], at a particular measured frequency k, can be represented by a rotating phasor, leading to the so-called circular motion analysis technique. Next, the two dimensional (2D) representation of the harmonic impedance phasors is then extended to a three-dimensional (3D) coordinate system by taking into account the frequency dependence. Finally, we introduce a new visualizing tool to summarize the frequency response behavior of ZPTV( jw, t) into a single 3D plot using the local Frenet-Serret frame. This novel 3D impedance representation is then compared with the 3D Nyquist representation of a PTV impedance. The concepts are illustrated through real measurements conducted on a PTV RC-circuit.

  10. Cardioprotective effect of Notch signaling on the development of myocardial infarction complicated by diabetes mellitus.

    Science.gov (United States)

    Wu, Fang; Yu, Bo; Zhang, Xu; Zhang, Yuelan

    2017-10-01

    The present study aimed to elucidate the role of Notch signaling in the development of myocardial infarction (MI) concomitant with diabetes in vivo and in vitro and evaluated the therapeutic effect of the Notch signaling in vitro. Streptozotocin-induced diabetic rats were subjected to 25 min of ischemia and 2 h of reperfusion. Cardiac troponin T (cTnT) and creatine kinase-MB (CK-MB) isoenzyme levels were detected. Infarct size was measured by 2,3,5-triphenyltetrazolium chloride staining. Myocardial apoptosis and fibrosis were examined by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling and Masson Trichrome staining, respectively. The mRNA and protein levels of Notch signaling components, including Notch1, Notch4, Delta-like 1, Jagged1, Mastermind-like protein 1 and p300, were quantified by reverse transcription-quantitative polymerase chain reaction and western blotting analyses, respectively. H9c2 cells were treated with/without 33 mM high glucose (HG) and/or subjected to hypoxia in the presence/absence of Jagged1. Cell viability and apoptosis were determined by MTT assay and Annexin V-fluorescein isothiocyanate/propidium iodide assay. Levels of the Notch signaling pathway members were examined. The present findings revealed that diabetes elevated CK-MB and cTnT, increased infarct size, induced myocardial apoptosis and inhibited the Notch signaling pathway in vivo after ischemia/reperfusion. Ischemia/reperfusion augmented the severity of MI in diabetic rats. Furthermore, HG reduced cell viability and induced cell apoptosis in H9c2 cells after hypoxia exposure, which was inhibited by Jagged1. We also found that HG inhibited Notch signaling in H9c2 cells after hypoxia, whereas Jagged1 exerted its cardioprotective effect on hypoxic injury (in HG environments or not) by activating the Notch signaling pathway. In conclusion, these findings suggest that diabetes promoted the progression of MI in vivo and in vitro via the inhibition of the Notch

  11. Excessive nitrite affects zebrafish valvulogenesis through yielding too much NO signaling.

    Directory of Open Access Journals (Sweden)

    Junbo Li

    Full Text Available Sodium nitrite, a common food additive, exists widely not only in the environment but also in our body. Excessive nitrite causes toxicological effects on human health; however, whether it affects vertebrate heart valve development remains unknown. In vertebrates, developmental defects of cardiac valves usually lead to congenital heart disease. To understand the toxic effects of nitrite on valvulogenesis, we exposed zebrafish embryos with different concentrations of sodium nitrite. Our results showed that sodium nitrite caused developmental defects of zebrafish heart dose dependently. It affected zebrafish heart development starting from 36 hpf (hour post fertilization when heart initiates looping process. Comprehensive analysis on the embryos at 24 hpf and 48 hpf showed that excessive nitrite did not affect blood circulation, vascular network, myocardium and endocardium development. But development of endocardial cells in atrioventricular canal (AVC of the embryos at 48 hpf was disrupted by too much nitrite, leading to defective formation of primitive valve leaflets at 76 hpf. Consistently, excessive nitrite diminished expressions of valve progenitor markers including bmp4, has2, vcana and notch1b at 48 hpf. Furthermore, 3', 5'-cyclic guanosine monophosphate (cGMP, downstream of nitric oxide (NO signaling, was increased its level significantly in the embryos exposed with excessive nitrite and microinjection of soluble guanylate cyclase inhibitor ODQ (1H-[1], [2], [4]Oxadiazolo[4,3-a] quinoxalin-1-one, an antagonist of NO signaling, into nitrite-exposed embryos could partly rescue the cardiac valve malformation. Taken together, our results show that excessive nitrite affects early valve leaflet formation by producing too much NO signaling.

  12. 17β-estradiol regulates the differentiation of cementoblasts via Notch signaling cascade

    Energy Technology Data Exchange (ETDEWEB)

    Liao, Jing; Zhou, Zeyuan; Huang, Li; Li, Yuyu [Department of Orthodontics, The State Key Laboratory of Oral Disease, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan Province (China); Li, Jingtao [Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan Province (China); Zou, Shujuan, E-mail: drzsj@scu.edu.cn [Department of Orthodontics, The State Key Laboratory of Oral Disease, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan Province (China)

    2016-08-12

    Estrogen has been well recognized as a key factor in the homeostasis of bone and periodontal tissue, but the way it regulates the activities of cementoblasts, the cell population maintaining cementum has not been fully understood. In this study, we examined the expression of estrogen receptor in OCCM-30 cells and the effect of 17β-estradiol (E2) on the proliferation and differentiation of OCCM-30 cells. We found that both estrogen receptor α and β were expressed in OCCM-30 cells. E2 exerted no significant influence on the proliferation of OCCM-30 cells, but inhibited the transcription and translation of BSP and Runx2 in the early phase of osteogenic induction except the BSP mRNA. Afterwards in the late phase of osteogenic induction, E2 enhanced the transcription and translation of BSP and Runx2 and promoted the calcium deposition. In addition, the expression level of Notch1, NICD and Hey1 mRNAs responded to exogenous E2 in a pattern similar to that of the osteoblastic markers. DAPT could attenuate the effect of E2 on the expression of osteoblastic markers. These findings indicated that E2 might regulate the differentiation of cementoblasts via Notch signaling. - Highlights: • 17β-estradiol showed no significant effect on the proliferation of cementoblasts. • 17β-estradiol promoted the osteoblastic differentiation of cementoblasts despite of an early transient inhibition. • Notch signaling was regulated by 17β-estradiol and was responsible for mediating the effect of E2 on cementoblasts. • Hey1 might display an opposite expression pattern to Notch signaling in certain circumstances.

  13. Simulated evolution of signal transduction networks.

    Directory of Open Access Journals (Sweden)

    Mohammad Mobashir

    Full Text Available Signal transduction is the process of routing information inside cells when receiving stimuli from their environment that modulate the behavior and function. In such biological processes, the receptors, after receiving the corresponding signals, activate a number of biomolecules which eventually transduce the signal to the nucleus. The main objective of our work is to develop a theoretical approach which will help to better understand the behavior of signal transduction networks due to changes in kinetic parameters and network topology. By using an evolutionary algorithm, we designed a mathematical model which performs basic signaling tasks similar to the signaling process of living cells. We use a simple dynamical model of signaling networks of interacting proteins and their complexes. We study the evolution of signaling networks described by mass-action kinetics. The fitness of the networks is determined by the number of signals detected out of a series of signals with varying strength. The mutations include changes in the reaction rate and network topology. We found that stronger interactions and addition of new nodes lead to improved evolved responses. The strength of the signal does not play any role in determining the response type. This model will help to understand the dynamic behavior of the proteins involved in signaling pathways. It will also help to understand the robustness of the kinetics of the output response upon changes in the rate of reactions and the topology of the network.

  14. Human papillomavirus 16E6 and NFX1-123 potentiate notch signaling and differentiation without activating cellular arrest

    Energy Technology Data Exchange (ETDEWEB)

    Vliet-Gregg, Portia A.; Hamilton, Jennifer R. [Center for Global Infectious Disease Research, Seattle Children' s Research Institute, 1900 Ninth Ave., Seattle, WA 98101 (United States); Katzenellenbogen, Rachel A., E-mail: rkatzen@uw.edu [Center for Global Infectious Disease Research, Seattle Children' s Research Institute, 1900 Ninth Ave., Seattle, WA 98101 (United States); Department of Pediatrics, Division of Adolescent Medicine, University of Washington, Seattle WA (United States)

    2015-04-15

    High-risk human papillomavirus (HR HPV) oncoproteins bind host cell proteins to dysregulate and uncouple apoptosis, senescence, differentiation, and growth. These pathways are important for both the viral life cycle and cancer development. HR HPV16 E6 (16E6) interacts with the cellular protein NFX1-123, and they collaboratively increase the growth and differentiation master regulator, Notch1. In 16E6 expressing keratinocytes (16E6 HFKs), the Notch canonical pathway genes Hes1 and Hes5 were increased with overexpression of NFX1-123, and their expression was directly linked to the activation or blockade of the Notch1 receptor. Keratinocyte differentiation genes Keratin 1 and Keratin 10 were also increased, but in contrast their upregulation was only indirectly associated with Notch1 receptor stimulation and was fully unlinked to growth arrest, increased p21{sup Waf1/CIP1}, or decreased proliferative factor Ki67. This leads to a model of 16E6, NFX1-123, and Notch1 differently regulating canonical and differentiation pathways and entirely uncoupling cellular arrest from increased differentiation. - Highlights: • 16E6 and NFX1-123 increased the Notch canonical pathway through Notch1. • 16E6 and NFX1-123 increased the differentiation pathway indirectly through Notch1. • 16E6 and NFX1-123 increased differentiation gene expression without growth arrest. • Increased NFX1-123 with 16E6 may create an ideal cellular phenotype for HPV.

  15. Multi-bearing weak defect detection for wayside acoustic diagnosis based on a time-varying spatial filtering rearrangement

    Science.gov (United States)

    Zhang, Shangbin; He, Qingbo; Ouyang, Kesai; Xiong, Wei

    2018-02-01

    The wayside Acoustic Defective Bearing Detector (ADBD) system plays an important role in ensuring the safety of railway transportation. However, Doppler distortion and multi-bearing source aliasing in the acquired acoustic bearing signals significantly decrease the accuracy of bearing diagnosis. Traditional multisource separation schemes using time-frequency filters constructed by a single microphone signal always show poor performance on weak signal separation. Inspired by an assumption that the spatial location of different sources is different, this paper proposes a novel time-varying spatial filtering rearrangement (TSFR) scheme based on a microphone array to overcome current difficulties. In the scheme, a zero-angle spatial filter and peak searching are proposed to obtain the time-centers of corresponding sources. Based on these time-centers, several time-varying spatial filters are designed to extract different source signals. Then interpolation and rearrangement are used to correct the Doppler distortion and reconstruct the corresponding separated signals. Finally, the train bearing fault diagnosis is implemented by analyzing the envelope spectrum of the corrected signals. Because the time-varying spatial filter construction is only dependent on the source location and has little relationship with the signal energy, the proposed TSFR scheme has significant advantages in weak signal separation and diagnosis in comparison with traditional ones. With the verifications by both simulation and experiment cases, the proposed array-based TSFR scheme shows a good performance on multiple fault source separation and is expected to be used in the ADBD system.

  16. Tangeretin has anti-asthmatic effects via regulating PI3K and Notch signaling and modulating Th1/Th2/Th17 cytokine balance in neonatal asthmatic mice

    Directory of Open Access Journals (Sweden)

    L.-L. Liu

    Full Text Available Asthma is a chronic allergic disease characterized by airway inflammation, airway hyper-responsiveness (AHR, and mucus hypersecretion. T-lymphocytes are involved in the pathogenesis of asthma, mediating airway inflammatory reactions by secreting cytokines. The phosphoinositide 3-kinase (PI3K and Notch signaling pathways are associated with T cell signaling, proliferation, and differentiation, and are important in the progression of asthma. Thus, compounds that can modulate T cell proliferation and function may be of clinical value. Here, we assessed the effects of tangeretin, a plant-derived flavonoid, in experimental asthma. BALB/c mice at postnatal day (P 12 were challenged with ovalbumin (OVA. Separate groups of mice (n=18/group were administered tangeretin at 25 or 50 mg/kg body weight by oral gavage. Dexamethasone was used as a positive control. Tangeretin treatment reduced inflammatory cell infiltration in bronchoalveolar lavage fluid (BALF and also restored the normal histology of lung tissues. OVA-specific IgE levels in serum and BALF were reduced. AHR, as determined by airway resistance and lung compliance, was normalized. Flow cytometry analyses revealed a reduced Th17 cell population. Tangeretin reduced the levels of Th2 and Th17 cytokines and raised IFN-γ levels. PI3K signaling was inhibited. The expressions of the Notch 1 receptor and its ligands Jagged 1 and 2 were downregulated by tangeretin. Our findings support the possible use of tangeretin for treating allergic asthma.

  17. Statistical Hierarchy of Varying Speed of Light Cosmologies

    Science.gov (United States)

    Salzano, Vincenzo; Da¸browski, Mariusz P.

    2017-12-01

    Many varying speed of light (VSL) theories have been developed recently. Here we address the issue of their observational verification in a fully comprehensive way. By using the most updated cosmological probes, we test three different candidates for a VSL theory (Barrow & Magueijo, Avelino & Martins, and Moffat). We consider many different Ansätze for both the functional form of c(z) and the dark energy dynamics. We compare these results using a reliable statistical tool such as the Bayesian evidence. We find that the present cosmological data are perfectly compatible with any of these VSL scenarios, but for the Moffat model there is a higher Bayesian evidence ratio in favor of VSL rather than the c = constant ΛCDM scenario. Moreover, in such a scenario, the VSL signal can help to strengthen constraints on the spatial curvature (with indication toward an open universe), to clarify some properties of dark energy (exclusion of a cosmological constant at 2σ level), and is also falsifiable in the near future owing to peculiar issues that differentiate this model from the standard one. Finally, we apply an information prior and entropy prior in order to put physical constraints on the models, though still in favor Moffat’s proposal.

  18. Perception of acoustically presented time series with varied intervals.

    Science.gov (United States)

    Wackermann, Jiří; Pacer, Jakob; Wittmann, Marc

    2014-03-01

    Data from three experiments on serial perception of temporal intervals in the supra-second domain are reported. Sequences of short acoustic signals ("pips") separated by periods of silence were presented to the observers. Two types of time series, geometric or alternating, were used, where the modulus 1+δ of the inter-pip series and the base duration Tb (range from 1.1 to 6s) were varied as independent parameters. The observers had to judge whether the series were accelerating, decelerating, or uniform (3 paradigm), or to distinguish regular from irregular sequences (2 paradigm). "Intervals of subjective uniformity" (isus) were obtained by fitting Gaussian psychometric functions to individual subjects' responses. Progression towards longer base durations (Tb=4.4 or 6s) shifts the isus towards negative δs, i.e., accelerating series. This finding is compatible with the phenomenon of "subjective shortening" of past temporal intervals, which is naturally accounted for by the lossy integration model of internal time representation. The opposite effect observed for short durations (Tb=1.1 or 1.5s) remains unexplained by the lossy integration model, and presents a challenge for further research. © 2013 Elsevier B.V. All rights reserved.

  19. Proinflammatory Cytokine Tumor Necrosis Factor (TNF)-like Weak Inducer of Apoptosis (TWEAK) Suppresses Satellite Cell Self-renewal through Inversely Modulating Notch and NF-κB Signaling Pathways*

    Science.gov (United States)

    Ogura, Yuji; Mishra, Vivek; Hindi, Sajedah M.; Kuang, Shihuan; Kumar, Ashok

    2013-01-01

    Satellite cell self-renewal is an essential process to maintaining the robustness of skeletal muscle regenerative capacity. However, extrinsic factors that regulate self-renewal of satellite cells are not well understood. Here, we demonstrate that TWEAK cytokine reduces the proportion of Pax7+/MyoD− cells (an index of self-renewal) on myofiber explants and represses multiple components of Notch signaling in satellite cell cultures. The number of Pax7+ cells is significantly increased in skeletal muscle of TWEAK knock-out (KO) mice compared with wild-type in response to injury. Furthermore, Notch signaling is significantly elevated in cultured satellite cells and in regenerating myofibers of TWEAK-KO mice. Forced activation of Notch signaling through overexpression of the Notch1 intracellular domain (N1ICD) rescued the TWEAK-mediated inhibition of satellite cell self-renewal. TWEAK also activates the NF-κB transcription factor in satellite cells and inhibition of NF-κB significantly improved the number of Pax7+ cells in TWEAK-treated cultures. Furthermore, our results demonstrate that a reciprocal interaction between NF-κB and Notch signaling governs the inhibitory effect of TWEAK on satellite cell self-renewal. Collectively, our study demonstrates that TWEAK suppresses satellite cell self-renewal through activating NF-κB and repressing Notch signaling. PMID:24151074

  20. LTβR signalling preferentially accelerates oncogenic AKT-initiated liver tumours.

    Science.gov (United States)

    Scarzello, Anthony J; Jiang, Qun; Back, Timothy; Dang, Hien; Hodge, Deborah; Hanson, Charlotte; Subleski, Jeffrey; Weiss, Jonathan M; Stauffer, Jimmy K; Chaisaingmongkol, Jitti; Rabibhadana, Siritida; Ruchirawat, Mathuros; Ortaldo, John; Wang, Xin Wei; Norris, Paula S; Ware, Carl F; Wiltrout, Robert H

    2016-10-01

    The relative contributions of inflammatory signalling and sequential oncogenic dysregulation driving liver cancer pathogenesis remain incompletely understood. Lymphotoxin-β receptor (LTβR) signalling is critically involved in hepatitis and liver tumorigenesis. Therefore, we explored the interdependence of inflammatory lymphotoxin signalling and specific oncogenic pathways in the progression of hepatic cancer. Pathologically distinct liver tumours were initiated by hydrodynamic transfection of oncogenic V-Akt Murine Thymoma Viral Oncogene Homolog 1 (AKT)/β-catenin or AKT/Notch expressing plasmids. To investigate the relationship of LTβR signalling and specific oncogenic pathways, LTβR antagonist (LTβR-Fc) or agonist (anti-LTβR) were administered post oncogene transfection. Initiated livers/tumours were investigated for changes in oncogene expression, tumour proliferation, progression, latency and pathology. Moreover, specific LTβR-mediated molecular events were investigated in human liver cancer cell lines and through transcriptional analyses of samples from patients with intrahepatic cholangiocarcinoma (ICC). AKT/β-catenin-transfected livers displayed increased expression of LTβ and LTβR, with antagonism of LTβR signalling reducing tumour progression and enhancing survival. Conversely, enforced LTβR-activation of AKT/β-catenin-initiated tumours induced robust increases in proliferation and progression of hepatic tumour phenotypes in an AKT-dependent manner. LTβR-activation also rapidly accelerated ICC progression initiated by AKT/Notch, but not Notch alone. Moreover, LTβR-accelerated development coincides with increases of Notch, Hes1, c-MYC, pAKT and β-catenin. We further demonstrate LTβR signalling in human liver cancer cell lines to be a regulator of Notch, pAKTser473 and β-catenin. Transcriptome analysis of samples from patients with ICC links increased LTβR network expression with poor patient survival, increased Notch1 expression and Notch

  1. Signal modulation as a mechanism for handicap disposal

    Science.gov (United States)

    Gavassa, Sat; Silva, Ana C.; Gonzalez, Emmanuel; Stoddard, Philip K.

    2012-01-01

    Signal honesty may be compromised when heightened competition provides incentive for signal exaggeration. Some degree of honesty might be maintained by intrinsic handicap costs on signalling or through imposition of extrinsic costs, such as social punishment of low quality cheaters. Thus, theory predicts a delicate balance between signal enhancement and signal reliability that varies with degree of social competition, handicap cost, and social cost. We investigated whether male sexual signals of the electric fish Brachyhypopomus gauderio would become less reliable predictors of body length when competition provides incentives for males to boost electric signal amplitude. As expected, social competition under natural field conditions and in controlled lab experiments drove males to enhance their signals. However, signal enhancement improved the reliability of the information conveyed by the signal, as revealed in the tightening of the relationship between signal amplitude and body length. Signal augmentation in male B. gauderio was independent of body length, and thus appeared not to be curtailed through punishment of low quality (small) individuals. Rather, all individuals boosted their signals under high competition, but those whose signals were farthest from the predicted value under low competition boosted signal amplitude the most. By elimination, intrinsic handicap cost of signal production, rather than extrinsic social cost, appears to be the basis for the unexpected reinforcement of electric signal honesty under social competition. Signal modulation may provide its greatest advantage to the signaller as a mechanism for handicap disposal under low competition rather than as a mechanism for exaggeration of quality under high competition. PMID:22665940

  2. An automated sawtooth detection algorithm for strongly varying plasma conditions and crash characteristics

    Science.gov (United States)

    Gude, A.; Maraschek, M.; Kardaun, O.; the ASDEX Upgrade Team

    2017-09-01

    A sawtooth crash algorithm that can automatically detect irregular sawteeth with strongly varying crash characteristics, including inverted crashes with central signal increase, has been developed. Such sawtooth behaviour is observed in ASDEX Upgrade with its tungsten wall, especially in phases with central ECRH. This application of ECRH for preventing impurity accumulation is envisaged also for ITER. The detection consists of three steps: a sensitive edge detection, a multichannel combination to increase detection performance, and a profile analysis that tests generic sawtooth crash features. The effect of detection parameters on the edge detection results has been investigated using synthetic signals and tested in an application to ASDEX Upgrade soft x-ray data.

  3. Nonstationary signals phase-energy approach-theory and simulations

    CERN Document Server

    Klein, R; Braun, S; 10.1006/mssp.2001.1398

    2001-01-01

    Modern time-frequency methods are intended to deal with a variety of nonstationary signals. One specific class, prevalent in the area of rotating machines, is that of harmonic signals of varying frequencies and amplitude. This paper presents a new adaptive phase-energy (APE) approach for time-frequency representation of varying harmonic signals. It is based on the concept of phase (frequency) paths and the instantaneous power spectral density (PSD). It is this path which represents the dynamic behaviour of the system generating the observed signal. The proposed method utilises dynamic filters based on an extended Nyquist theorem, enabling extraction of signal components with optimal signal-to-noise ratio. The APE detects the most energetic harmonic components (frequency paths) in the analysed signal. Tests on simulated signals show the superiority of the APE in resolution and resolving power as compared to STFT and wavelets wave- packet decomposition. The dynamic filters also enable the reconstruction of the ...

  4. Calcium signaling in taste cells.

    Science.gov (United States)

    Medler, Kathryn F

    2015-09-01

    The sense of taste is a common ability shared by all organisms and is used to detect nutrients as well as potentially harmful compounds. Thus taste is critical to survival. Despite its importance, surprisingly little is known about the mechanisms generating and regulating responses to taste stimuli. All taste responses depend on calcium signals to generate appropriate responses which are relayed to the brain. Some taste cells have conventional synapses and rely on calcium influx through voltage-gated calcium channels. Other taste cells lack these synapses and depend on calcium release to formulate an output signal through a hemichannel. Beyond establishing these characteristics, few studies have focused on understanding how these calcium signals are formed. We identified multiple calcium clearance mechanisms that regulate calcium levels in taste cells as well as a calcium influx that contributes to maintaining appropriate calcium homeostasis in these cells. Multiple factors regulate the evoked taste signals with varying roles in different cell populations. Clearly, calcium signaling is a dynamic process in taste cells and is more complex than has previously been appreciated. This article is part of a Special Issue entitled: 13th European Symposium on Calcium. Copyright © 2014 Elsevier B.V. All rights reserved.

  5. ADAPTIVE NOISE CANCELLATION OF DOPPLER SHIFTED SIGNALS: A LINEAR FRAMEWORK

    OpenAIRE

    Stewart, R. W.; Weiss, S.

    1996-01-01

    In this paper we investigate the performance of single channel adaptive noise cancellation techniques for situations where the noise signal received by the two microphones cannot be related by a fixed weight canceller's (linear) digital filter due to Doppler shift on the two signals. A mathematical signal model is produced, which shows that the adaptive filter is in fact required to identify a time-varying system which incorporates Doppler shift, and potential rapid variations in signal power...

  6. Time-varying trends of global vegetation activity

    Science.gov (United States)

    Pan, N.; Feng, X.; Fu, B.

    2016-12-01

    Vegetation plays an important role in regulating the energy change, water cycle and biochemical cycle in terrestrial ecosystems. Monitoring the dynamics of vegetation activity and understanding their driving factors have been an important issue in global change research. Normalized Difference Vegetation Index (NDVI), an indicator of vegetation activity, has been widely used in investigating vegetation changes at regional and global scales. Most studies utilized linear regression or piecewise linear regression approaches to obtain an averaged changing rate over a certain time span, with an implicit assumption that the trend didn't change over time during that period. However, no evidence shows that this assumption is right for the non-linear and non-stationary NDVI time series. In this study, we adopted the multidimensional ensemble empirical mode decomposition (MEEMD) method to extract the time-varying trends of NDVI from original signals without any a priori assumption of their functional form. Our results show that vegetation trends are spatially and temporally non-uniform during 1982-2013. Most vegetated area exhibited greening trends in the 1980s. Nevertheless, the area with greening trends decreased over time since the early 1990s, and the greening trends have stalled or even reversed in many places. Regions with browning trends were mainly located in southern low latitudes in the 1980s, whose area decreased before the middle 1990s and then increased at an accelerated rate. The greening-to-browning reversals were widespread across all continents except Oceania (43% of the vegetated areas), most of which happened after the middle 1990s. In contrast, the browning-to-greening reversals occurred in smaller area and earlier time. The area with monotonic greening and browning trends accounted for 33% and 5% of the vegetated area, respectively. By performing partial correlation analyses between NDVI and climatic elements (temperature, precipitation and cloud cover

  7. Continuous-time signals

    CERN Document Server

    Shmaliy, Yuriy

    2006-01-01

    Gives a modern description of continuous-time deterministic signals Signal formation techniquesTime vs. frequency and frequency vs. time analysisCorrelation and energy analysisNarrowband signals and sampling.

  8. Time-varying output performances of piezoelectric vibration energy harvesting under nonstationary random vibrations

    Science.gov (United States)

    Yoon, Heonjun; Kim, Miso; Park, Choon-Su; Youn, Byeng D.

    2018-01-01

    Piezoelectric vibration energy harvesting (PVEH) has received much attention as a potential solution that could ultimately realize self-powered wireless sensor networks. Since most ambient vibrations in nature are inherently random and nonstationary, the output performances of PVEH devices also randomly change with time. However, little attention has been paid to investigating the randomly time-varying electroelastic behaviors of PVEH systems both analytically and experimentally. The objective of this study is thus to make a step forward towards a deep understanding of the time-varying performances of PVEH devices under nonstationary random vibrations. Two typical cases of nonstationary random vibration signals are considered: (1) randomly-varying amplitude (amplitude modulation; AM) and (2) randomly-varying amplitude with randomly-varying instantaneous frequency (amplitude and frequency modulation; AM-FM). In both cases, this study pursues well-balanced correlations of analytical predictions and experimental observations to deduce the relationships between the time-varying output performances of the PVEH device and two primary input parameters, such as a central frequency and an external electrical resistance. We introduce three correlation metrics to quantitatively compare analytical prediction and experimental observation, including the normalized root mean square error, the correlation coefficient, and the weighted integrated factor. Analytical predictions are in an excellent agreement with experimental observations both mechanically and electrically. This study provides insightful guidelines for designing PVEH devices to reliably generate electric power under nonstationary random vibrations.

  9. 14-3-3{sigma} controls corneal epithelial cell proliferation and differentiation through the Notch signaling pathway

    Energy Technology Data Exchange (ETDEWEB)

    Xin, Ying [Stem Cell Institute, James Brown Cancer Center, University of Louisville School of Medicine, 301 E. Muhammad Ali Blvd., Louisville, KY 40202 (United States); Department of Ophthalmology and Visual Sciences, University of Louisville School of Medicine, 301 E. Muhammad Ali Blvd., Louisville, KY 40202 (United States); Lu, Qingxian [Tumor Immunobiology Group, James Brown Cancer Center, University of Louisville School of Medicine, 301 E. Muhammad Ali Blvd., Louisville, KY 40202 (United States); Department of Ophthalmology and Visual Sciences, University of Louisville School of Medicine, 301 E. Muhammad Ali Blvd., Louisville, KY 40202 (United States); Department of Biochemistry and Molecular Biology, University of Louisville School of Medicine, 301 E. Muhammad Ali Blvd., Louisville, KY 40202 (United States); Li, Qiutang, E-mail: q.li@louisville.edu [Stem Cell Institute, James Brown Cancer Center, University of Louisville School of Medicine, 301 E. Muhammad Ali Blvd., Louisville, KY 40202 (United States); Department of Ophthalmology and Visual Sciences, University of Louisville School of Medicine, 301 E. Muhammad Ali Blvd., Louisville, KY 40202 (United States)

    2010-02-19

    14-3-3{sigma} (also called stratifin) is specifically expressed in the stratified squamous epithelium and its function was recently shown to be linked to epidermal stratification and differentiation in the skin. In this study, we investigated its role in corneal epithelium cell proliferation and differentiation. We showed that the 14-3-3{sigma} mutation in repeated epilation (Er) mutant mice results in a dominant negative truncated protein. Primary corneal epithelial cells expressing the dominant negative protein failed to undergo high calcium-induced cell cycle arrest and differentiation. We further demonstrated that blocking endogenous 14-3-3{sigma} activity in corneal epithelial cells by overexpressing dominative negative 14-3-3{sigma} led to reduced Notch activity and Notch1/2 transcription. Significantly, expression of the active Notch intracellular domain overcame the block in epithelial cell differentiation in 14-3-3{sigma} mutant-expressing corneal epithelial cells. We conclude that 14-3-3{sigma} is critical for regulating corneal epithelial proliferation and differentiation by regulating Notch signaling activity.

  10. PKCα Attenuates Jagged-1-mediated Notch Signaling in ErbB-2 positive Breast Cancer to Reverse Trastuzumab Resistance

    Science.gov (United States)

    Pandya, Kinnari; Wyatt, Debra; Gallagher, Brian; Shah, Deep; Baker, Andrew; Bloodworth, Jeffrey; Zlobin, Andrei; Pannuti, Antonio; Green, Andrew; Ellis, Ian O.; Filipovic, Aleksandra; Sagert, Jason; Rana, Ajay; Albain, Kathy S.; Miele, Lucio; Denning, Mitchell F.; Osipo, Clodia

    2015-01-01

    Purpose Breast cancer is the second leading cause of cancer mortality among women worldwide. The major problem with current treatments is tumor resistance, recurrence, and disease progression. ErbB-2 positive breast tumors are aggressive and frequently become resistant to trastuzumab or lapatinib. We showed previously that Notch-1 is required for trastuzumab resistance in ErbB-2 positive breast cancer. Experimental Design Here, we sought to elucidate mechanisms by which ErbB-2 attenuates Notch signaling and how this is reversed by trastuzumab or lapatinib. Results The current study elucidates a novel Notch inhibitory mechanism by which PKCα downstream of ErbB-2: 1. Restricts the availability of Jagged-1 at the cell surface to trans activate Notch; 2. Restricts the critical interaction between Jagged-1 and Mindbomb-1, an E3 ligase that is required for Jagged-1 ubiquitinylation and subsequent Notch activation; 3. Reverses trastuzumab resistance in vivo; and 4. Predicts better outcome in women with ErbB-2 positive breast cancer. Conclusions The clinical impact of these studies is PKCα is potentially a good prognostic marker for low Notch activity and increased trastuzumab sensitivity in ErbB-2 positive breast cancer. Moreover, women with ErbB-2 positive breast tumors expressing high Notch activation and low PKCα expression could be the best candidates for anti-Notch therapy. PMID:26350262

  11. Basic digital signal processing

    CERN Document Server

    Lockhart, Gordon B

    1985-01-01

    Basic Digital Signal Processing describes the principles of digital signal processing and experiments with BASIC programs involving the fast Fourier theorem (FFT). The book reviews the fundamentals of the BASIC program, continuous and discrete time signals including analog signals, Fourier analysis, discrete Fourier transform, signal energy, power. The text also explains digital signal processing involving digital filters, linear time-variant systems, discrete time unit impulse, discrete-time convolution, and the alternative structure for second order infinite impulse response (IIR) sections.

  12. Bearing detection in the presence of two sources of varying coherence using the complex cepstrum

    Science.gov (United States)

    Fuller, C. R.; Elliott, K. B.

    1987-01-01

    The effect of the presence of two acoustic sources (one, the primary, whose location is to be detected) of varying coherence on a cepstral bearing finding procedure is experimentally studied. The coherence between the acoustic sources was altered by adding random noise of various SNR (signal-to-noise ratio) to the input signal of the primary source; the same base signal being fed to both sources. The results demonstrate that, when block liftering is used, the primary source bearing is reliably estimated for coherences as low as gamma sup 2 greater than or approx equal to 0.5. The results also imply that background noise (unreflected) of SNR greater than or approx equal to 10 dB will not markedly affect the accuracy of the bearing estimation algorithm.

  13. Time Frequency Features of Rotor Systems with Slowly Varying Mass

    Directory of Open Access Journals (Sweden)

    Tao Yu

    2011-01-01

    Full Text Available With the analytic method and numerical method respectively, the asymptotic solutions and finite element model of rotor system with single slowly varying mass is obtained to investigate the time frequency features of such rotor system; furthermore, with given model of slowly varying mass, the rotor system with dual slowly varying mass is studied. For the first order approximate solution is used, there exists difference between the results with analytic method and numerical method. On the base of common characteristics of rotor system with dual slowly varying mass, the general rules and formula describing the frequency distribution of rotor system with multiple slowly varying mass are proposed.

  14. Optical signal to noise ratio improvement through unbalanced noise beating in phase-sensitive parametric amplifiers

    OpenAIRE

    Malik, R; Kumpera, A.; Olsson, S. L. I.; Andrekson, P.A.; Karlsson, M

    2014-01-01

    We investigate the beating of signal and idler waves, which have imbalanced signal to noise ratios, in a phase-sensitive parametric amplifier. Imbalanced signal to noise ratios are achieved in two ways; first by imbalanced noise loading; second by varying idler to signal input power ratio. In the case of imbalanced noise loading the phase-sensitive amplifier improved the signal to noise ratio from 3 to 6 dB, and in the case of varying idler to signal input power ratio, the signal to noise rat...

  15. A Synthetic Triterpenoid CDDO-Im Inhibits Tumorsphere Formation by Regulating Stem Cell Signaling Pathways in Triple-Negative Breast Cancer

    Science.gov (United States)

    Wahler, Joseph; Liby, Karen T.; Sporn, Michael B.; Suh, Nanjoo

    2014-01-01

    Triple-negative breast cancer is associated with poor prognosis because of a high rate of tumor recurrence and metastasis. Previous studies demonstrated that the synthetic triterpenoid, CDDO-Imidazolide (CDDO-Im) induced cell cycle arrest and apoptosis in triple-negative breast cancer. Since a small subpopulation of cancer stem cells has been suggested to be responsible for drug resistance and metastasis of tumors, our present study determined whether the effects of CDDO-Im in triple-negative breast cancer are due to the inhibition of a cancer stem cell subpopulation. CDDO-Im treatment markedly induced cell cycle arrest at G2/M-phase and apoptosis in the triple-negative breast cancer cell lines, SUM159 and MDA-MB-231. Because SUM159 cells were more sensitive to CDDO-Im than MDA-MB-231 cells, the effects of CDDO-Im on the cancer stem cell subpopulation were further investigated in SUM159 cells. SUM159 cells formed tumorspheres in culture, and the cancer stem cell subpopulation, CD24−/EpCAM+ cells, was markedly enriched in SUM159 tumorspheres. The CD24−/EpCAM+ cells in SUM159 tumorspheres were significantly inhibited by CDDO-Im treatment. CDDO-Im also significantly decreased sphere forming efficiency and tumorsphere size in both primary and secondary sphere cultures. PCR array of stem cell signaling genes showed that expression levels of many key molecules in the stem cell signaling pathways, such as Notch, TGF-β/Smad, Hedgehog and Wnt, were significantly down-regulated by CDDO-Im in SUM159 tumorspheres. Protein levels of Notch receptors (c-Notch1, Notch1 and Notch3), TGF-β/Smad (pSmad2/3) and Hedgehog downstream effectors (GLI1) also were markedly reduced by CDDO-Im. In conclusion, the present study demonstrates that the synthetic triterpenoid, CDDO-Im, is a potent anti-cancer agent against triple-negative breast cancer cells by targeting the cancer stem cell subpopulation. PMID:25229616

  16. Multivariate Analysis for the Processing of Signals

    Directory of Open Access Journals (Sweden)

    Beattie J.R.

    2014-01-01

    Full Text Available Real-world experiments are becoming increasingly more complex, needing techniques capable of tracking this complexity. Signal based measurements are often used to capture this complexity, where a signal is a record of a sample’s response to a parameter (e.g. time, displacement, voltage, wavelength that is varied over a range of values. In signals the responses at each value of the varied parameter are related to each other, depending on the composition or state sample being measured. Since signals contain multiple information points, they have rich information content but are generally complex to comprehend. Multivariate Analysis (MA has profoundly transformed their analysis by allowing gross simplification of the tangled web of variation. In addition MA has also provided the advantage of being much more robust to the influence of noise than univariate methods of analysis. In recent years, there has been a growing awareness that the nature of the multivariate methods allows exploitation of its benefits for purposes other than data analysis, such as pre-processing of signals with the aim of eliminating irrelevant variations prior to analysis of the signal of interest. It has been shown that exploiting multivariate data reduction in an appropriate way can allow high fidelity denoising (removal of irreproducible non-signals, consistent and reproducible noise-insensitive correction of baseline distortions (removal of reproducible non-signals, accurate elimination of interfering signals (removal of reproducible but unwanted signals and the standardisation of signal amplitude fluctuations. At present, the field is relatively small but the possibilities for much wider application are considerable. Where signal properties are suitable for MA (such as the signal being stationary along the x-axis, these signal based corrections have the potential to be highly reproducible, and highly adaptable and are applicable in situations where the data is noisy or

  17. Modelling discontinuous well log signal to identify lithological ...

    Indian Academy of Sciences (India)

    Identification of sharp and discontinuous lithological boundaries from well log signal stemming fromheterogeneous subsurface structures assumes a special significance in geo-exploration studies. Well logdata acquired from various geological settings generally display nonstationary/nonlinear characteristicswith varying ...

  18. Digital signal processing laboratory

    CERN Document Server

    Kumar, B Preetham

    2011-01-01

    INTRODUCTION TO DIGITAL SIGNAL PROCESSING Brief Theory of DSP ConceptsProblem SolvingComputer Laboratory: Introduction to MATLAB®/SIMULINK®Hardware Laboratory: Working with Oscilloscopes, Spectrum Analyzers, Signal SourcesDigital Signal Processors (DSPs)ReferencesDISCRETE-TIME LTI SIGNALS AND SYSTEMS Brief Theory of Discrete-Time Signals and SystemsProblem SolvingComputer Laboratory: Simulation of Continuous Time and Discrete-Time Signals and Systems ReferencesTIME AND FREQUENCY ANALYSIS OF COMMUNICATION SIGNALS Brief Theory of Discrete-Time Fourier Transform (DTFT), Discrete Fourier Transform

  19. Inhibition of Notch signaling enhances transdifferentiation of the esophageal squamous epithelium towards a Barrett's-like metaplasia via KLF4.

    Science.gov (United States)

    Vega, Maria E; Giroux, Véronique; Natsuizaka, Mitsuteru; Liu, Mingen; Klein-Szanto, Andres J; Stairs, Douglas B; Nakagawa, Hiroshi; Wang, Kenneth K; Wang, Timothy C; Lynch, John P; Rustgi, Anil K

    2014-01-01

    Barrett's esophagus (BE) is defined as an incomplete intestinal metaplasia characterized generally by the presence of columnar and goblet cells in the formerly stratified squamous epithelium of the esophagus. BE is known as a precursor for esophageal adenocarcinoma. Currently, the cell of origin for human BE has yet to be clearly identified. Therefore, we investigated the role of Notch signaling in the initiation of BE metaplasia. Affymetrix gene expression microarray revealed that BE samples express decreased levels of Notch receptors (NOTCH2 and NOTCH3) and one of the the ligands (JAG1). Furthermore, BE tissue microarray showed decreased expression of NOTCH1 and its downstream target HES1. Therefore, Notch signaling was inhibited in human esophageal epithelial cells by expression of dominant-negative-Mastermind-like (dnMAML), in concert with MYC and CDX1 overexpression. Cell transdifferentiation was then assessed by 3D organotypic culture and evaluation of BE-lineage specific gene expression. Notch inhibition promoted transdifferentiation of esophageal epithelial cells toward columnar-like cells as demonstrated by increased expression of columnar keratins (K8, K18, K19, K20) and glandular mucins (MUC2, MUC3B, MUC5B, MUC17) and decreased expression of squamous keratins (K5, K13, K14). In 3D culture, elongated cells were observed in the basal layer of the epithelium with Notch inhibition. Furthermore, we observed increased expression of KLF4, a potential driver of the changes observed by Notch inhibition. Interestingly, knockdown of KLF4 reversed the effects of Notch inhibition on BE-like metaplasia. Overall, Notch signaling inhibition promotes transdifferentiation of esophageal cells toward BE-like metaplasia in part via upregulation of KLF4. These results support a novel mechanism through which esophageal epithelial transdifferentiation promotes the evolution of BE.

  20. Spatial and temporal disparity in signals and maskers affects signal detection in non-human primates.

    Science.gov (United States)

    Rocchi, Francesca; Dylla, Margit E; Bohlen, Peter A; Ramachandran, Ramnarayan

    2017-02-01

    Detection thresholds for auditory stimuli (signals) increase in the presence of maskers. Natural environments contain maskers/distractors that can have a wide range of spatiotemporal properties relative to the signal. While these parameters have been well explored psychophysically in humans, they have not been well explored in animal models, and their neuronal underpinnings are not well understood. As a precursor to the neuronal measurements, we report the effects of systematically varying the spatial and temporal relationship between signals and noise in macaque monkeys (Macaca mulatta and Macaca radiata). Macaques detected tones masked by noise in a Go/No-Go task in which the spatiotemporal relationships between the tone and noise were systematically varied. Masked thresholds were higher when the masker was continuous or gated on and off simultaneously with the signal, and lower when the continuous masker was turned off during the signal. A burst of noise caused higher masked thresholds if it completely temporally overlapped with the signal, whereas partial overlap resulted in lower thresholds. Noise durations needed to be at least 100 ms before significant masking could be observed. Thresholds for short duration tones were significantly higher when the onsets of signal and masker coincided compared to when the signal was presented during the steady state portion of the noise (overshoot). When signal and masker were separated in space, masked signal detection thresholds decreased relative to when the masker and signal were co-located (spatial release from masking). Masking release was larger for azimuthal separations than for elevation separations. These results in macaques are similar to those observed in humans, suggesting that the specific spatiotemporal relationship between signal and masker determine threshold in natural environments for macaques in a manner similar to humans. These results form the basis for future investigations of neuronal correlates and

  1. Hepatitis C Virus Core Protein Modulates Endoglin (CD105) Signaling Pathway for Liver Pathogenesis.

    Science.gov (United States)

    Kwon, Young-Chan; Sasaki, Reina; Meyer, Keith; Ray, Ranjit

    2017-11-01

    Endoglin is part of the TGF-β receptor complex and has a crucial role in fibrogenesis and angiogenesis. It is also an important protein for tumor growth, survival, and cancer cell metastasis. In a previous study, we have shown that hepatitis C virus (HCV) infection induces epithelial-mesenchymal transition (EMT) state and cancer stem-like cell (CSC) properties in human hepatocytes. Our array data suggested that endoglin (CD105) mRNA is significantly upregulated in HCV-associated CSCs. In this study, we have observed increased endoglin expression on the cell surface of an HCV core-expressing hepatocellular carcinoma (HepG2) cell line or immortalized human hepatocytes (IHH) and activation of its downstream signaling molecules. The status of phospho-SMAD1/5 and the expression of inhibitor of DNA binding protein 1 (ID1) were upregulated in HCV-infected cells or viral core gene-transfected cells. Additionally, we observed upregulation of endoglin/ID1 mRNA expression in chronic HCV patient liver biopsy samples. CSC generation by HCV core protein was dependent on the endoglin signaling pathway using activin receptor-like kinase 1 (ALK1) Fc blocking peptide and endoglin small interfering RNA (siRNA). Further, follow-up from in vitro analysis suggested that the antiapoptosis Bcl2 protein, proliferation-related cyclin D1 protein, and CSC-associated Hes1, Notch1, Nanog, and Sox2 proteins are enhanced during infection or ectopic expression of HCV core protein. IMPORTANCE Endoglin plays a crucial role in fibrogenesis and angiogenesis and is an important protein for tumor growth, survival, and cancer cell metastasis. Endoglin enhances ALK1-SMAD1/5 signaling in different cell types, leading to increased proliferation and migration responses. We have observed endoglin expression on the HCV core-expressing cell surface of human hepatocyte origin and activation of phospho-SMAD1/5 and ID1 downstream signaling molecules. ID1 protein plays a role in CSC properties, and we found that

  2. Vector-field statistics for the analysis of time varying clinical gait data.

    Science.gov (United States)

    Donnelly, C J; Alexander, C; Pataky, T C; Stannage, K; Reid, S; Robinson, M A

    2017-01-01

    In clinical settings, the time varying analysis of gait data relies heavily on the experience of the individual(s) assessing these biological signals. Though three dimensional kinematics are recognised as time varying waveforms (1D), exploratory statistical analysis of these data are commonly carried out with multiple discrete or 0D dependent variables. In the absence of an a priori 0D hypothesis, clinicians are at risk of making type I and II errors in their analyis of time varying gait signatures in the event statistics are used in concert with prefered subjective clinical assesment methods. The aim of this communication was to determine if vector field waveform statistics were capable of providing quantitative corroboration to practically significant differences in time varying gait signatures as determined by two clinically trained gait experts. The case study was a left hemiplegic Cerebral Palsy (GMFCS I) gait patient following a botulinum toxin (BoNT-A) injection to their left gastrocnemius muscle. When comparing subjective clinical gait assessments between two testers, they were in agreement with each other for 61% of the joint degrees of freedom and phases of motion analysed. For tester 1 and tester 2, they were in agreement with the vector-field analysis for 78% and 53% of the kinematic variables analysed. When the subjective analyses of tester 1 and tester 2 were pooled together and then compared to the vector-field analysis, they were in agreement for 83% of the time varying kinematic variables analysed. These outcomes demonstrate that in principle, vector-field statistics corroborates with what a team of clinical gait experts would classify as practically meaningful pre- versus post time varying kinematic differences. The potential for vector-field statistics to be used as a useful clinical tool for the objective analysis of time varying clinical gait data is established. Future research is recommended to assess the usefulness of vector-field analyses

  3. The influence of temporally varying noise from seismic air guns on the detection of underwater sounds by seals.

    Science.gov (United States)

    Sills, Jillian M; Southall, Brandon L; Reichmuth, Colleen

    2017-02-01

    Standard audiometric data are often applied to predict how noise influences hearing. With regard to auditory masking, critical ratios-obtained using tonal signals and flat-spectrum maskers-can be combined with noise spectral density levels derived from 1/3-octave band levels to predict signal amplitudes required for detection. However, the efficacy of this conventional model of masking may vary based on features of the signal and noise in question. The ability of resource managers to quantify masking from intermittent seismic noise is relevant due to widespread geophysical exploration. To address this, spotted and ringed seals with previously measured critical ratios were trained to detect low-frequency tonal signals within seismic pulses recorded 1 and 30 km from an operational air gun array. The conventional model of masking accurately predicted the extent of masking only in certain cases. When noise amplitude varied significantly in time, the results suggested that detection was driven by higher signal-to-noise ratios within time windows shorter than the full signal duration. This study evaluates when it is appropriate to use average noise levels and critical ratios to predict auditory masking experienced by marine mammals, and suggests how masking models can be improved by incorporating time-based analyses of signals and noise.

  4. Estimating varying coefficients for partial differential equation models.

    Science.gov (United States)

    Zhang, Xinyu; Cao, Jiguo; Carroll, Raymond J

    2017-09-01

    Partial differential equations (PDEs) are used to model complex dynamical systems in multiple dimensions, and their parameters often have important scientific interpretations. In some applications, PDE parameters are not constant but can change depending on the values of covariates, a feature that we call varying coefficients. We propose a parameter cascading method to estimate varying coefficients in PDE models from noisy data. Our estimates of the varying coefficients are shown to be consistent and asymptotically normally distributed. The performance of our method is evaluated by a simulation study and by an empirical study estimating three varying coefficients in a PDE model arising from LIDAR data. © 2017, The International Biometric Society.

  5. Methods for time-varying exposure related problems in pharmacoepidemiology

    DEFF Research Database (Denmark)

    Pazzagli, Laura; Linder, Marie; Zhang, Mingliang

    2017-01-01

    PURPOSE: Lack of control for time-varying exposures can lead to substantial bias in estimates of treatment effects. The aim of this study is to provide an overview and guidance on some of the available methodologies used to address problems related to time-varying exposure and confounding...... pharmacoepidemiological problems, construction of treatment episodes, time-varying confounders, cumulative exposure and latency, and treatment switching. RESULTS: A correct treatment episodes construction is fundamental to avoid bias in treatment effect estimates. Several methods exist to address time-varying covariates...

  6. Dynamic Programming based Time-Delay Estimation (TDE) Technique for Analysis of Time-varying Time-delay

    CERN Document Server

    Gupta, Deepak K; Fonck, Raymond R

    2008-01-01

    A new time-delay estimation (TDE) technique based on dynamic programming is developed, to measures the time-varying time-delay between two signals. Dynamic programming based TDE technique provides a frequency response 5 to 10 times higher than previously known TDE techniques, namely those based on time-lag cross-correlation or wavelet analysis. Effects of frequency spectrum, signal-to-noise ratio and amplitude of time-delay on response (represented as transfer function) of TDE technique is studied using simulated data signals. Transfer function for the technique decreases with increase in noise in signal; however it is independent of signal spectrum shape. Dynamic programming based TDE technique is applied to the Beam-Emission-Spectroscopy (BES) diagnostic data to measure poloidal velocity fluctuations, which led to the observation of theoretically predicted zonal flows in high-temperature tokamak plasmas.

  7. Alterations in Notch signalling in skeletal muscles from mdx and dko dystrophic mice and patients with Duchenne muscular dystrophy.

    Science.gov (United States)

    Church, Jarrod E; Trieu, Jennifer; Chee, Annabel; Naim, Timur; Gehrig, Stefan M; Lamon, Séverine; Angelini, Corrado; Russell, Aaron P; Lynch, Gordon S

    2014-04-01

    New Findings What is the central question of this study? The Notch signalling pathway plays an important role in muscle regeneration, and activation of the pathway has been shown to enhance muscle regeneration in aged mice. It is unknown whether Notch activation will have a similarly beneficial effect on muscle regeneration in the context of Duchenne muscular dystrophy (DMD). What is the main finding and its importance? Although expression of Notch signalling components is altered in both mouse models of DMD and in human DMD patients, activation of the Notch signalling pathway does not confer any functional benefit on muscles from dystrophic mice, suggesting that other signalling pathways may be more fruitful targets for manipulation in treating DMD. Abstract In Duchenne muscular dystrophy (DMD), muscle damage and impaired regeneration lead to progressive muscle wasting, weakness and premature death. The Notch signalling pathway represents a central regulator of gene expression and is critical for cellular proliferation, differentiation and apoptotic signalling during all stages of embryonic muscle development. Notch activation improves muscle regeneration in aged mice, but its potential to restore regeneration and function in muscular dystrophy is unknown. We performed a comprehensive examination of several genes involved in Notch signalling in muscles from dystrophin-deficient mdx and dko (utrophin- and dystrophin-null) mice and DMD patients. A reduction of Notch1 and Hes1 mRNA in tibialis anterior muscles of dko mice and quadriceps muscles of DMD patients and a reduction of Hes1 mRNA in the diaphragm of the mdx mice were observed, with other targets being inconsistent across species. Activation and inhibition of Notch signalling, followed by measures of muscle regeneration and function, were performed in the mouse models of DMD. Notch activation had no effect on functional regeneration in C57BL/10, mdx or dko mice. Notch inhibition significantly depressed the

  8. Leptin-Notch signaling axis is involved in pancreatic cancer progression.

    Science.gov (United States)

    Harbuzariu, Adriana; Rampoldi, Antonio; Daley-Brown, Danielle S; Candelaria, Pierre; Harmon, Tia L; Lipsey, Crystal C; Beech, Derrick J; Quarshie, Alexander; Ilies, Gabriela Oprea; Gonzalez-Perez, Ruben R

    2017-01-31

    Pancreatic cancer (PC) shows a high death rate. PC incidence and prognosis are affected by obesity, a pandemic characterized by high levels of leptin. Notch is upregulated by leptin in breast cancer. Thus, leptin and Notch crosstalk could influence PC progression. Here we investigated in PC cell lines (BxPC-3, MiaPaCa-2, Panc-1, AsPC-1), derived tumorspheres and xenografts whether a functional leptin-Notch axis affects PC progression and expansion of pancreatic cancer stem cells (PCSC). PC cells and tumorspheres were treated with leptin and inhibitors of Notch (gamma-secretase inhibitor, DAPT) and leptin (iron oxide nanoparticle-leptin peptide receptor antagonist 2, IONP-LPrA2). Leptin treatment increased cell cycle progression and proliferation, and the expression of Notch receptors, ligands and targeted molecules (Notch1-4, DLL4, JAG1, Survivin and Hey2), PCSC markers (CD24/CD44/ESA, ALDH, CD133, Oct-4), ABCB1 protein, as well as tumorsphere formation. Leptin-induced effects on PC and tumorspheres were decreased by IONP-LPrA2 and DAPT. PC cells secreted leptin and expressed the leptin receptor, OB-R, which indicates a leptin autocrine/paracrine signaling loop could also affect tumor progression. IONP-LPrA2 treatment delayed the onset of MiaPaCa-2 xenografts, and decreased tumor growth and the expression of proliferation and PCSC markers. Present data suggest that leptin-Notch axis is involved in PC. PC has no targeted therapy and is mainly treated with chemotherapy, whose efficiency could be decreased by leptin and Notch activities. Thus, the leptin-Notch axis could be a novel therapeutic target, particularly for obese PC patients.

  9. NOR1 promotes hepatocellular carcinoma cell proliferation and migration through modulating the Notch signaling pathway

    Energy Technology Data Exchange (ETDEWEB)

    You, Kun; Sun, Peisheng; Yue, Zhongyi; Li, Jian; Xiong, Wancheng; Wang, Jianguo, E-mail: jianguowangjgw@163.com

    2017-03-15

    Hepatocellular carcinoma (HCC) is one of the most common malignant tumors worldwide. Previous studies have reported that the oxidored-nitro domain containing protein 1 (NOR1) is a novel tumor suppressor in several tumors. Recent evidence suggests that NOR1 is strongly expressed in HCC cells. However, its role and mechanism in HCC are unclear. In the current study, Western blot and qPCR detected strong NOR1 mRNA and protein expression in HepG2 and Hep3B cells. After transfection with NOR1 siRNA or pcDNA3.1-myc-his-NOR1, the proliferation and migration of HepG2 and Hep3B cells were analyzed in vitro. HepG2 or Hep3B cells overexpressing NOR1 showed an increased proliferation and migration, whereas siRNA-mediated silencing of NOR1 showed the opposite effect. Furthermore, NOR1 activated the Notch signaling pathway, indicated by increased levels of Notch1, NICD, Hes1, and Hey1 in protein. Importantly, the Notch inhibitor DAPT downregulated Notch activation and further enhanced siNOR1-induced reduction of cell proliferation and migration in HepG2 and Hep3B cells, whereas DAPT reversed the effect of NOR1 overexpression on cell proliferation and migration. In conclusion, these results indicate that NOR1 may be involved in the progression of HCC and thus may be a potential target for the treatment of liver cancer. - Highlights: • NOR1 expression is up-regulated in HCC cells. • NOR1 promotes the proliferation and migration of HCC cells. • NOR1 promotes the progression of HCC cells by activating Notch pathway.

  10. Reciprocal upregulation of Notch signaling molecules in hematopoietic progenitor and mesenchymal stromal cells

    Directory of Open Access Journals (Sweden)

    Kikuchi Y

    2011-01-01

    Full Text Available Although mesenchymal stem cells (MSCs play pivotal supportive roles in hematopoiesis, how they interact with hematopoietic stem cells (HSCs is not well understood. We investigated the interaction between HSCs and surrogate MSCs (C3H10T1/2 stromal cells, focusing on the molecular events induced by cell contact of these bipartite populations. C3H10T1/2 is a mesenchymal stromal cell line that can be induced to differentiate into preadipocytes (A54 and myoblasts (M1601. The stromal cell derivatives were cocultured with murine HSCs (Lineage-Sca1+, and gene expression profiles in stromal cells and HSCs were compared before and after the coculture. HSCs gave rise to cobblestone areas only on A54 cells, with ninefold more progenitors than on M1601 or undifferentiated C3H10T1/2 cells. Microarray-based screening and a quantitative reverse transcriptase directed-polymerase chain reaction showed that the levels of Notch ligands (Jagged1 and Delta-like 3 were increased in A54 cells upon interaction with HSCs. On the other hand, the expression of Notch1 and Hes1 was upregulated in the HSCs cocultured with A54 cells. A transwell assay revealed that the reciprocal upregulation was dependent on cell-to-cell contact. The result suggested that in the hematopoietic niche, HSCs help MSCs to produce Notch ligands, and in turn, MSCs help HSCs to express Notch receptor. Such a reciprocal upregulation would reinforce the downstream signaling to determine the fate of hematopoietic cell lineage. Clarification of the initiating events on cell contact should lead to the identification of specific molecular targets to facilitate HSC engraftment in transplantation therapy.

  11. Notch signaling pathway targeted therapy suppresses tumor progression and metastatic spread in pancreatic cancer.

    Science.gov (United States)

    Yabuuchi, Shinichi; Pai, Shweta G; Campbell, Nathaniel R; de Wilde, Roeland F; De Oliveira, Elizabeth; Korangath, Preethi; Streppel, Mirte M; Rasheed, Zeshaan A; Hidalgo, Manuel; Maitra, Anirban; Rajeshkumar, N V

    2013-07-10

    Pancreatic ductal adenocarcinoma (PDA) remains a lethal human malignancy with historically limited success in treatment. The role of aberrant Notch signaling, which requires the constitutive activation of γ-secretase, in the initiation and progression of PDA is well defined and inhibitors of this pathway are currently in clinical trials. Here we investigated the in vivo therapeutic effect of PF-03084014, a selective γ-secretase inhibitor, alone and in combination with gemcitabine in pancreatic cancer xenografts. PF-03084014 treatment inhibited the cleavage of nuclear Notch 1 intracellular domain and Notch targets Hes-1 and Hey-1. Gemcitabine treatment showed good response but not capable of inducing tumor regressions and targeting the tumor-resident cancer stem cells (CD24(+)CD44(+) and ALDH(+) tumor cells). A combination of PF-03084014 and gemcitabine treatment resulted tumor regression in 3 of 4 subcutaneously implanted xenograft models. PF-03084014, and in combination with gemcitabine reduced putative cancer stem cells, indicating that PF-03084014 target the especially dangerous and resilient cancer stem cells within pancreatic tumors. Tumor re-growth curves plotted after drug treatments demonstrated that the effect of the combination therapy was sustainable than that of gemcitabine. Notably, in a highly aggressive orthotopic model, PF-03084014 and gemcitabine combination was effective in inducing apoptosis, inhibition of tumor cell proliferation and angiogenesis, resulting in the attenuation of primary tumor growth as well as controlling metastatic dissemination, compared to gemcitabine treatment. In summary, our preclinical data suggest that PF-03084014 has greater anti-tumor activity in combination with gemcitabine in PDA and provides rationale for further investigation of this combination in PDA. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  12. Optimum short-time polynomial regression for signal analysis

    Indian Academy of Sciences (India)

    We propose a short-time polynomial regression (STPR) for time-varying signal analysis. The advantage of using polynomials is that the notion of a spectrum is not needed and the signals can be analyzed in the time domain over short durations. In the presence of noise, such modeling becomes important, because the ...

  13. Statistical issues in signal extraction from microarrays

    Science.gov (United States)

    Bergemann, Tracy; Quiaoit, Filemon; Delrow, Jeffrey J.; Zhao, Lue Ping

    2001-06-01

    Microarray technologies are increasingly used in biomedical research to study genome-wide expression profiles in the post genomic era. Their popularity is largely due to their high throughput and economical affordability. For example, microarrays have been applied to studies of cell cycle, regulatory circuitry, cancer cell lines, tumor tissues, and drug discoveries. One obstacle facing the continued success of applying microarray technologies, however, is the random variaton present on microarrays: within signal spots, between spots and among chips. In addition, signals extracted by available software packages seem to vary significantly. Despite a variety of software packages, it appears that there are two major approaches to signal extraction. One approach is to focus on the identification of signal regions and hence estimation of signal levels above background levels. The other approach is to use the distribution of intensity values as a way of identifying relevant signals. Building upon both approaches, the objective of our work is to develop a method that is statistically rigorous and also efficient and robust. Statistical issues to be considered here include: (1) how to refine grid alignment so that the overall variation is minimized, (2) how to estimate the signal levels relative to the local background levels as well as the variance of this estimate, and (3) how to integrate red and green channel signals so that the ratio of interest is stable, simultaneously relaxing distributional assumptions.

  14. Time-varying interaction leads to amplitude death in coupled ...

    Indian Academy of Sciences (India)

    A new form of time-varying interaction in coupled oscillators is introduced. In this interaction, each individual oscillator has always time-independent self-feedback while its interaction with other oscillators are modulated with time-varying function. This interaction gives rise to a phenomenon called amplitude death even in ...

  15. Linear Parameter Varying Control of Doubly Fed Induction Machines

    NARCIS (Netherlands)

    Tien, H. Nguyen; Scherer, Carsten W.; Scherpen, Jacquelien M.A.; Müller, Volkmar

    This paper is concerned with the design of a self-scheduled current controller for doubly fed induction machines. The design is based on the framework of linear parameter-varying systems where the mechanical angular speed is considered to be a measurable time-varying parameter. The objective is to

  16. Surface sealing and hydraulic conductances under varying-intensity rains

    NARCIS (Netherlands)

    Giménez, D.; Dirksen, C.; Miedema, R.; Eppink, L.A.A.J.; Schoonderbeek, D.

    1992-01-01

    In the past, investigations on surface seals developing under simulated rains usually were performed with uniform rainfall intensities. Recent studies, however, showed that varying-intensity rains affect erosion and volumes of runoff. We conducted a study on surface sealing under varying-intensity

  17. Expected optimal feedback with Time-Varying Parameters

    NARCIS (Netherlands)

    Tucci, M.P.; Kendrick, D.A.; Amman, H.M.|info:eu-repo/dai/nl/070970777

    2011-01-01

    In this paper we derive the closed loop form of the Expected Optimal Feedback rule, sometimes called passive learning stochastic control, with time varying parameters. As such this paper extends the work of Kendrick (1981,2002, Chapter 6) where parameters are assumed to vary randomly around a known

  18. Specimen loading list for the varying temperature experiment

    Energy Technology Data Exchange (ETDEWEB)

    Qualls, A.L.; Sitterson, R.G. [Oak Ridge National Lab., TN (United States)

    1998-09-01

    The varying temperature experiment HFIR-RB-13J has been assembled and inserted in the reactor. Approximately 5300 specimens were cleaned, inspected, matched, and loaded into four specimen holders. A listing of each specimen loaded into the steady temperature holder, its position in the capsule, and the identification of the corresponding specimen loaded into the varying temperature holder is presented in this report.

  19. How Do Parenting Concepts Vary within and between the Families?

    Science.gov (United States)

    Roskam, Isabelle; Meunier, Jean Christophe

    2009-01-01

    How do parenting concepts vary within and between the families? The present study regards parenting as a complex family process by considering three concepts of parenting: styles, differential treatment and coparenting consistency. A main question was addressed: whether and how these parenting concepts vary within the families towards siblings or…

  20. Time varying voltage combustion control and diagnostics sensor

    Science.gov (United States)

    Chorpening, Benjamin T [Morgantown, WV; Thornton, Jimmy D [Morgantown, WV; Huckaby, E David [Morgantown, WV; Fincham, William [Fairmont, WV

    2011-04-19

    A time-varying voltage is applied to an electrode, or a pair of electrodes, of a sensor installed in a fuel nozzle disposed adjacent the combustion zone of a continuous combustion system, such as of the gas turbine engine type. The time-varying voltage induces a time-varying current in the flame which is measured and used to determine flame capacitance using AC electrical circuit analysis. Flame capacitance is used to accurately determine the position of the flame from the sensor and the fuel/air ratio. The fuel and/or air flow rate (s) is/are then adjusted to provide reduced flame instability problems such as flashback, combustion dynamics and lean blowout, as well as reduced emissions. The time-varying voltage may be an alternating voltage and the time-varying current may be an alternating current.

  1. Basic fibroblast growth factor/vascular endothelial growth factor in the serum from severe burn patients stimulates the proliferation of cultured human umbilical cord mesenchymal stem cells via activation of Notch signaling pathways.

    Science.gov (United States)

    Liu, Ling-Ying; Hou, Yu-Sen; Chai, Jia-Ke; Hu, Quan; Duan, Hong-Jie; Yu, Yong-Hui; Yin, Hui-Nan; Hao, Dai-Feng; Feng, Guang; Li, Tao; Du, Jun-Dong

    2013-11-01

    Mesenchymal stem cells (MSCs) are the leading cellular constituents used in regenerative medicine. MSCs repair and reconstruct wounds of acute traumata and radiation-induced burns through proliferation, differentiation, and trophic activity. However, repair effect of MSCs on severe burn wounds remain to be clarified because severe burns are much more complex traumata than radiation-induced burns. Survival and proliferation of MSCs in microenvironments affected by severe burns are very important for improving wound repair/regeneration. This study aimed to elucidate the survival and proliferation effects and the potential proliferation mechanism of serum from severe burn patients (BPS) on human umbilical cord MSCs (hUCMSCs) in vitro. The hUCMSCs were isolated, cultured, and identified. Next, we evaluated the effects of BPS on cell numbers, cell cycle progression, cyclin D expression, and key proteins and genes of the Notch signaling pathway. Putative mechanisms underlying the proliferation of hUCMSCs were investigated. BPS markedly increased the number of hUCMSCs, and the results of the cell cycle studies indicated that BPS induced cell cycle progression into the M phase. Cyclin D expression was higher with BPS than in the control group. Moreover, Notch-1, a key determinant of hUCMSC activation and proliferation, and its target gene Hes-1 were overexpressed after BPS treatment. Proliferation numbers of hUCMSC, rate of proliferation period (G2/M+S), and the expression of cyclin D, Notch-1, and Hes-1 were markedly decreased by Notch signaling inhibitors (DAPT/GSI). In the case of BPS, basic fibroblast growth factor and vascular endothelial growth factor were the key factors that promoted hUCMSC proliferation. This study provides novel evidence for the role of BPS in the survival and rapid proliferation of hUCMSCs and suggests that these cells could be used for cell therapy-based clinical applications for treating severe burns. Furthermore, hUCMSC proliferation was

  2. Signal sciences workshop proceedings

    Energy Technology Data Exchange (ETDEWEB)

    Candy, J.V.

    1997-05-01

    This meeting is aimed primarily at signal processing and controls. The technical program for the 1997 Workshop includes a variety of efforts in the Signal Sciences with applications in the Microtechnology Area a new program at LLNL and a future area of application for both Signal/Image Sciences. Special sessions organized by various individuals in Seismic and Optical Signal Processing as well as Micro-Impulse Radar Processing highlight the program, while the speakers at the Signal Processing Applications session discuss various applications of signal processing/control to real world problems. For the more theoretical, a session on Signal Processing Algorithms was organized as well as for the more pragmatic, featuring a session on Real-Time Signal Processing.

  3. Retinoid signalling during embryogenesis

    NARCIS (Netherlands)

    Pijnappel, W.W.M.; Hendriks, H.F.J.; Durston, A.J.

    1996-01-01

    Conclusion: Retinoids are suspected to have multiple functions during embryogenesis, which are carried out via various different signal transduction pathways involving active retinoids and nuclear retinoid receptors. Research focuses on the identification of the retinoid signal transduction

  4. Apparatus and method for characterizing ultrafast polarization varying optical pulses

    Science.gov (United States)

    Smirl, A.; Trebino, R.P.

    1999-08-10

    Practical techniques are described for characterizing ultrafast potentially ultraweak, ultrashort optical pulses. The techniques are particularly suited to the measurement of signals from nonlinear optical materials characterization experiments, whose signals are generally too weak for full characterization using conventional techniques. 2 figs.

  5. Biomedical signal processing

    CERN Document Server

    Akay, Metin

    1994-01-01

    Sophisticated techniques for signal processing are now available to the biomedical specialist! Written in an easy-to-read, straightforward style, Biomedical Signal Processing presents techniques to eliminate background noise, enhance signal detection, and analyze computer data, making results easy to comprehend and apply. In addition to examining techniques for electrical signal analysis, filtering, and transforms, the author supplies an extensive appendix with several computer programs that demonstrate techniques presented in the text.

  6. Tetrapyrrole Signaling in Plants

    Directory of Open Access Journals (Sweden)

    Robert M. Larkin

    2016-10-01

    Full Text Available Tetrapyrroles make critical contributions to a number of important processes in diverse organisms. In plants, tetrapyrroles are essential for light signaling, the detoxification of reactive oxygen species, the assimilation of nitrate and sulfate, respiration, photosynthesis, and programed cell death. Thus, it is not surprising that tetrapyrrole metabolism is strictly regulated and that tetrapyrrole metabolism affects signaling mechanisms that regulate gene expression. In plants and algae, tetrapyrroles are synthesized in plastids and were some of the first plastid signals demonstrated to regulate nuclear gene expression. In plants, the mechanism of tetrapyrrole-dependent plastid-to-nucleus signaling remains poorly understood. Additionally, some of experiments that tested ideas for possible signaling mechanisms appeared to produce conflicting data. In some instances, these conflicts are potentially explained by different experimental conditions. Although the biological function of tetrapyrrole signaling is poorly understood, there is compelling evidence that this signaling is significant. Specifically, this signaling appears to affect the accumulation of starch and may promote abiotic stress tolerance. Tetrapyrrole-dependent plastid-to-nucleus signaling interacts with a distinct plastid-to-nucleus signaling mechanism that depends on GENOMES UNCUOPLED1 (GUN1. GUN1 contributes to a variety of processes, such as chloroplast biogenesis, the circadian rhythm, abiotic stress tolerance, and development. Thus, the contribution of tetrapyrrole signaling to plant function is potentially broader than we currently appreciate. In this review, I discuss these aspects of tetrapyrrole signaling.

  7. Growth factor signalling

    NARCIS (Netherlands)

    De Laat, SW; Boonstra, J; Defize, LHK; Kruijer, W; Van der Saag, PT; Tertoolen, LGJ; Van Zoelen, JJ; Den Hertog, J

    1999-01-01

    Signalling between cells in the developing vertebrate embryo is essential for nomal embryonic development. In the mid 1970's, signal transduction research started at the Hubrecht Laboratory with special emphasis on analysis of the signalling mechanisms that direct cell proliferation and

  8. A new measuring and identification approach for time-varying bioimpedance using multisine electrical impedance spectroscopy.

    Science.gov (United States)

    Sanchez, B; Louarroudi, E; Jorge, E; Cinca, J; Bragos, R; Pintelon, R

    2013-03-01

    The bioimpedance measurement/identification of time-varying biological systems Z(ω, t) by means of electrical impedance spectroscopy (EIS) is still a challenge today. This paper presents a novel measurement and identification approach, the so-called parametric-in-time approach, valid for time-varying (bio-)impedance systems with a (quasi) periodic character. The technique is based on multisine EIS. Contrary to the widely used nonparametric-in-time strategy, the (bio-)impedance Z(ω, t) is assumed to be time-variant during the measurement interval. Therefore, time-varying spectral analysis tools are required. This new parametric-in-time measuring/identification technique has experimentally been validated through three independent sets of in situ measurements of in vivo myocardial impedance. We show that the time-varying myocardial impedance Z(ω, t) is dominantly periodically time varying (PTV), denoted as ZPTV(ω, t). From the temporal analysis of ZPTV(ω, t), we demonstrate that it is possible to decompose ZPTV(ω, t) into a(n) (in)finite sum of fundamental (bio-)impedance spectra, the so-called harmonic impedance spectra (HIS) Zk(ω)s with [Formula: see text]. This is similar to the well-known Fourier series of a periodic signal, but now understood at the level of a periodic system's frequency response. The HIS Zk(ω)s for [Formula: see text] actually summarize in the bi-frequency (ω, k) domain all the temporal in-cycle information about the periodic changes of Z(ω, t). For the particular case k = 0 (i.e. on the ω-axis), Z0(ω) reflects the mean in-cycle behavior of the time-varying bioimpedance. Finally, the HIS Zk(ω)s are directly identified from noisy current and voltage myocardium measurements at the multisine measurement frequencies (i.e. nonparametric-in-frequency).

  9. Model-free adaptive fractional order control of stable linear time-varying systems.

    Science.gov (United States)

    Yakoub, Z; Amairi, M; Chetoui, M; Saidi, B; Aoun, M

    2017-03-01

    This paper presents a new model-free adaptive fractional order control approach for linear time-varying systems. An online algorithm is proposed to determine some frequency characteristics using a selective filtering and to design a fractional PID controller based on the numerical optimization of the frequency-domain criterion. When the system parameters are time-varying, the controller is updated to keep the same desired performances. The main advantage of the proposed approach is that the controller design depends only on the measured input and output signals of the process. The effectiveness of the proposed method is assessed through a numerical example. Copyright © 2017 ISA. Published by Elsevier Ltd. All rights reserved.

  10. Active-Varying Sampling-Based Fault Detection Filter Design for Networked Control Systems

    Directory of Open Access Journals (Sweden)

    Yu-Long Wang

    2014-01-01

    Full Text Available This paper is concerned with fault detection filter design for continuous-time networked control systems considering packet dropouts and network-induced delays. The active-varying sampling period method is introduced to establish a new discretized model for the considered networked control systems. The mutually exclusive distribution characteristic of packet dropouts and network-induced delays is made full use of to derive less conservative fault detection filter design criteria. Compared with the fault detection filter design adopting a constant sampling period, the proposed active-varying sampling-based fault detection filter design can improve the sensitivity of the residual signal to faults and shorten the needed time for fault detection. The simulation results illustrate the merits and effectiveness of the proposed fault detection filter design.

  11. Dual-pump Kerr Micro-cavity Optical Frequency Comb with varying FSR spacing

    Science.gov (United States)

    Wang, Weiqiang; Chu, Sai T.; Little, Brent E.; Pasquazi, Alessia; Wang, Yishan; Wang, Leiran; Zhang, Wenfu; Wang, Lei; Hu, Xiaohong; Wang, Guoxi; Hu, Hui; Su, Yulong; Li, Feitao; Liu, Yuanshan; Zhao, Wei

    2016-01-01

    In this paper, we demonstrate a novel dual-pump approach to generate robust optical frequency comb with varying free spectral range (FSR) spacing in a CMOS-compatible high-Q micro-ring resonator (MRR). The frequency spacing of the comb can be tuned by an integer number FSR of the MRR freely in our dual-pump scheme. The dual pumps are self-oscillated in the laser cavity loop and their wavelengths can be tuned flexibly by programming the tunable filter embedded in the cavity. By tuning the pump wavelength, broadband OFC with the bandwidth of >180 nm and the frequency-spacing varying from 6 to 46-fold FSRs is realized at a low pump power. This approach could find potential and practical applications in many areas, such as optical metrology, optical communication, and signal processing systems, for its excellent flexibility and robustness. PMID:27338250

  12. Spectrum Sensing Based on Censored Observations in Time-Varying Channels using AR-1 Model

    Directory of Open Access Journals (Sweden)

    Dhaval K Patel

    2015-01-01

    Full Text Available Non-parametric sensing algorithms are preferred in cognitive radio. In this paper, spectrum sensing method based on censored observations is proposed. We evaluate the performance of Censored Anderson-Darling (CAD sensing method in time-varying and flat-fading channel using Monte Carlo simulations. We have shown the performance of the CAD sensing in terms of receiver operating characteristic (ROC. The considered channel is modeled by Gaussian variables and characterized by a first ordered autoregressive process ($AR1$. It is shown that the proposed method outperforms prevailing techniques such as the Energy detection (ED sensing and  Order-statistic (OS based sensing in time-varying channel at lower signal to noise ratio.

  13. The Signal Distribution System

    CERN Document Server

    Belohrad, D; CERN. Geneva. AB Department

    2005-01-01

    For the purpose of LHC signal observation and high frequency signal distribution, the Signal Distribution System (SDS) was built. The SDS can contain up to 5 switching elements, where each element allows the user to switch between one of the maximum 8 bi-directional signals. The coaxial relays are used to switch the signals. Depending of the coaxial relay type used, the transfer bandwidth can go up to 18GHz. The SDS is controllable via TCP/IP, parallel port, or locally by rotary switch.

  14. High-fat diet feeding promotes stemness and precancerous changes in murine gastric mucosa mediated by leptin receptor signaling pathway.

    Science.gov (United States)

    Arita, Seiya; Kinoshita, Yuta; Ushida, Kaori; Enomoto, Atsushi; Inagaki-Ohara, Kyoko

    2016-11-15

    Obesity increases the risk for gastric cancers. However, the occurrence and mechanisms of precancerous atrophic gastritis induced by high-fat diet (HFD) remain unclear. Here, we show that HFD-associated lipotoxicity induces precancerous lesions that are accompanied by the disruption of organelle homeostasis, tissue integrity, and deregulated expression of stemness genes in the gastric epithelium mediated by leptin receptor (ObR) signaling. Following HFD feeding, ectopic fat accumulated and expression of LAMP2A in lysosome and COX IV in mitochondria increased in the gastric mucosa. HFD feeding also led to enhanced expression of activated-Notch1 and stem cell markers Lgr5, CD44, and EpCAM. In addition, HFD-fed mice showed intracellular β-catenin accumulation in the gastric mucosa with increased expression of its target genes, Nanog, Oct4, and c-Myc. These observations were abrogated in the leptin-deficient ob/ob mice and ObR-mutated db/db mice, indicating that these HFD-induced changes were responsible for effects downstream of the ObR. Consistent with this, the expression of the Class IA and III PI3Ks was increased following ObR activation in the gastric mucosa of HFD-fed mice. Together, these results suggest that HFD-induced lipotoxicity and deregulated organelle biosynthesis confer cancer stem cell-like properties to the gastric mucosa via signaling pathway mediated by leptin, PI3K and β-catenin. Copyright © 2016 Elsevier Inc. All rights reserved.

  15. Influence of feeding varying crude protein and digestible energy ...

    African Journals Online (AJOL)

    Influence of feeding varying crude protein and digestible energy levels on the development of individual muscles, rate of lean and fat deposition in pigs reared from 9 to 60kg liveweight in a humid tropical environment.

  16. Uus Eesti film pandi eile Karlovy Varys projektorisse / Kristiina Davidjants

    Index Scriptorium Estoniae

    Davidjants, Kristiina, 1974-

    2008-01-01

    8. juulil esilinastus Karlovy Vary filmifestivalil Rene Vilbre noortefilm "Mina olin siin", mille aluseks on Sass Henno romaan "Mina olin siin. Esimene arest". Film võistleb võistlusprogrammis "East of the West"

  17. Modeling non-Gaussian time-varying vector autoregressive process

    Data.gov (United States)

    National Aeronautics and Space Administration — We present a novel and general methodology for modeling time-varying vector autoregressive processes which are widely used in many areas such as modeling of chemical...

  18. Toluene metabolism during exposure to varying concentrations combined with exercise

    DEFF Research Database (Denmark)

    Bælum, Jesper; Døssing, M; Hansen, S H

    1987-01-01

    The urinary excretion of hippuric acid (HA) and ortho-cresol (O-cr) in man was measured in two studies of 7-h exposure to toluene in a climate chamber, either constant concentration of 100 ppm or varying concentrations containing peaks of 300 ppm but with a time-weighted average of 100 ppm....... In Study A, four males were exposed to clean air and to constant and varying concentrations of toluene in combination with rest and with 100 W exercise in 140 min. Exercise increased end exposure excretion rate of HA and O-cr by 47 and 114%, respectively. After exposure, all excess HA was excreted within 4...... h, while O-cr was eliminated with a half life of about 3 h. Alveolar air concentration of toluene varied between 21 and 31 ppm during constant exposure and between 13 and 57 ppm during varying exposure, but no difference in mean alveolar toluene concentration or in metabolite excretion was seen...

  19. A Semiparametric Recurrent Events Model with Time-varying Coefficients

    Science.gov (United States)

    Yu, Zhangsheng; Liu, Lei; Bravata, Dawn M.; Williams, Linda S.; Tepper, Robert S.

    2013-01-01

    SUMMARY We consider a recurrent events model with time-varying coefficients motivated by two clinical applications. A random effects (Gaussian frailty) model is used to describe the intensity of recurrent events. The model can accommodate both time-varying and time-constant coefficients. The penalized spline method is used to estimate the time-varying coefficients. Laplace approximation is used to evaluate the penalized likelihood without a closed form. The smoothing parameters are estimated in a similar way to variance components. We conduct simulations to evaluate the performance of the estimates for both time-varying and time-independent coefficients. We apply this method to analyze two data sets: a stroke study and a child wheeze study. PMID:22903343

  20. Quality of Eggs Under Varying Storage Periods, Conditions and ...

    African Journals Online (AJOL)

    Quality of Eggs Under Varying Storage Periods, Conditions and Seasons in ... and egg weight on external and internal characteristics of chicken eggs. ... Storage time did not affect (p>0.05) shell weight, shape index, egg length and egg width.

  1. Analysis of time-varying psoriasis lesion image patterns

    DEFF Research Database (Denmark)

    Maletti, Gabriela Mariel; Ersbøll, Bjarne Kjær; Nielsen, Allan Aasbjerg

    2004-01-01

    The multivariate alteration detection transform is applied to pairs of within and between time varying registered psoriasis image patterns. Color band contribution to the variates explaining maximal change is analyzed....

  2. Gut microbiomes of Indian children of varying nutritional status

    National Research Council Canada - National Science Library

    Ghosh, Tarini Shankar; Gupta, Sourav Sen; Bhattacharya, Tanudeep; Yadav, Deepak; Barik, Anamitra; Chowdhury, Abhijit; Das, Bhabatosh; Mande, Sharmila S; Nair, G Balakrish

    2014-01-01

    .... Consequently, dysbiosis of the gut microbiota has been implicated in malnutrition. Metagenomics approach was adopted to investigate the gut microbiome sampled from 20 rural Indian children with varying nutritional status...

  3. Signal Processing Methods Monitor Cranial Pressure

    Science.gov (United States)

    2010-01-01

    Dr. Norden Huang, of Goddard Space Flight Center, invented a set of algorithms (called the Hilbert-Huang Transform, or HHT) for analyzing nonlinear and nonstationary signals that developed into a user-friendly signal processing technology for analyzing time-varying processes. At an auction managed by Ocean Tomo Federal Services LLC, licenses of 10 U.S. patents and 1 domestic patent application related to HHT were sold to DynaDx Corporation, of Mountain View, California. DynaDx is now using the licensed NASA technology for medical diagnosis and prediction of brain blood flow-related problems, such as stroke, dementia, and traumatic brain injury.

  4. Design of 2D Time-Varying Vector Fields

    KAUST Repository

    Chen, Guoning

    2012-10-01

    Design of time-varying vector fields, i.e., vector fields that can change over time, has a wide variety of important applications in computer graphics. Existing vector field design techniques do not address time-varying vector fields. In this paper, we present a framework for the design of time-varying vector fields, both for planar domains as well as manifold surfaces. Our system supports the creation and modification of various time-varying vector fields with desired spatial and temporal characteristics through several design metaphors, including streamlines, pathlines, singularity paths, and bifurcations. These design metaphors are integrated into an element-based design to generate the time-varying vector fields via a sequence of basis field summations or spatial constrained optimizations at the sampled times. The key-frame design and field deformation are also introduced to support other user design scenarios. Accordingly, a spatial-temporal constrained optimization and the time-varying transformation are employed to generate the desired fields for these two design scenarios, respectively. We apply the time-varying vector fields generated using our design system to a number of important computer graphics applications that require controllable dynamic effects, such as evolving surface appearance, dynamic scene design, steerable crowd movement, and painterly animation. Many of these are difficult or impossible to achieve via prior simulation-based methods. In these applications, the time-varying vector fields have been applied as either orientation fields or advection fields to control the instantaneous appearance or evolving trajectories of the dynamic effects. © 1995-2012 IEEE.

  5. Electricity futures prices: time varying sensitivity to fundamentals

    OpenAIRE

    Fleten, Stein-Erik; Huisman, Ronald; Kilic, Mehtap; Pennings, Enrico; Westgaard, Sjur

    2014-01-01

    This paper provides insight into the time-varying relation between electricity futures prices and fundamentals in the form of contract prices for fossil fuels. As supply curves are not constant and different producers have different marginal costs of production, we argue that the relation between the prices of electricity futures and those of underlying fundamentals such as natural gas, coal and emission rights varies over time. We test this view by applying a model that linearly relates elec...

  6. Bounds and asymptotics for orthogonal polynomials for varying weights

    CERN Document Server

    Levin, Eli

    2018-01-01

    This book establishes bounds and asymptotics under almost minimal conditions on the varying weights, and applies them to universality limits and entropy integrals.  Orthogonal polynomials associated with varying weights play a key role in analyzing random matrices and other topics.  This book will be of use to a wide community of mathematicians, physicists, and statisticians dealing with techniques of potential theory, orthogonal polynomials, approximation theory, as well as random matrices. .

  7. NOTCH4 signaling controls EFNB2-induced endothelial progenitor cell dysfunction in preeclampsia.

    Science.gov (United States)

    Liu, Xiaoxia; Luo, Qingqing; Zheng, Yanfang; Liu, Xiaoping; Hu, Ying; Liu, Weifang; Luo, Minglian; Zhao, Yin; Zou, Li

    2016-07-01

    Preeclampsia is a serious complication of pregnancy and is closely related to endothelial dysfunction, which can be repaired by endothelial progenitor cells (EPCs). The DLL4/NOTCH-EFNB2 (ephrinB2) cascade may be involved in the pathogenesis of preeclampsia by inhibiting the biological activity of EPCs. In addition, both NOTCH1 and NOTCH4, which are specific receptors for DLL4/NOTCH, play critical roles in the various steps of angiogenesis. However, it has not been determined which receptor (NOTCH1, NOTCH4, or both) is specific for the DLL4/NOTCH-EFNB2 cascade. Accordingly, we performed a series of investigations to evaluate it. EFNB2 expression was examined when NOTCH4 or NOTCH1 was downregulated, with or without DLL4 treatment. Then, the effects of NOTCH4 on EPC function were detected. Additionally, we analyzed NOTCH4 and EFNB2 expression in the EPCs from preeclampsia and normal pregnancies. Results showed that NOTCH4 downregulation led to decreased expression of EFNB2, which maintained the same level in the presence of DLL4/NOTCH activation. By contrast, NOTCH1 silencing resulted in a moderate increase in EFNB2 expression, which further increased in the presence of DLL4/NOTCH activation. The downregulation of NOTCH4 resulted in an increase of EPC biological activity, which was similar to EFNB2 silencing. NOTCH4 expression, consistent with the EFNB2 level, increased notably in preeclampsia EPCs compared with the controls. These findings suggest that NOTCH4, not NOTCH1, is the specific receptor for the DLL4/NOTCH-EFNB2 cascade. Blockade of this cascade may enhance the angiogenic property of EPCs, and act as a potential target to promote angiogenesis in patients with preeclampsia. © 2016 Society for Reproduction and Fertility.

  8. Superluminal Signal Velocity

    OpenAIRE

    Nimtz, Guenter

    1998-01-01

    It recently has been demonstrated that signals conveyed by evanescent modes can travel faster than light. In this report some special features of signals are introduced and investigated, for instance the fundamental property that signals are frequency band limited. Evanescent modes are characterized by extraordinary properties: Their energy is {\\it negative}, they are not directly measurable, and the evanescent region is not causal since the modes traverse this region instantaneously. The stu...

  9. Noncausal Superluminal Nonlocal Signalling

    OpenAIRE

    Srikanth, R.

    1999-01-01

    We propose a thought experiment for classical superluminal signal transmission based on the quantum nonlocal influence of photons on their momentum entangled EPR twins. The signal sender measures either position or momentum of particles in a pure ensemble of the entangled pairs, leaving their twins as localized particles or plane waves. The signal receiver distinguishes these outcomes interferometrically using a double slit interferometer modified by a system of optical filters. Since the col...

  10. Digital signal processing

    CERN Document Server

    O'Shea, Peter; Hussain, Zahir M

    2011-01-01

    In three parts, this book contributes to the advancement of engineering education and that serves as a general reference on digital signal processing. Part I presents the basics of analog and digital signals and systems in the time and frequency domain. It covers the core topics: convolution, transforms, filters, and random signal analysis. It also treats important applications including signal detection in noise, radar range estimation for airborne targets, binary communication systems, channel estimation, banking and financial applications, and audio effects production. Part II considers sel

  11. Biomedical signals and systems

    CERN Document Server

    Tranquillo, Joseph V

    2013-01-01

    Biomedical Signals and Systems is meant to accompany a one-semester undergraduate signals and systems course. It may also serve as a quick-start for graduate students or faculty interested in how signals and systems techniques can be applied to living systems. The biological nature of the examples allows for systems thinking to be applied to electrical, mechanical, fluid, chemical, thermal and even optical systems. Each chapter focuses on a topic from classic signals and systems theory: System block diagrams, mathematical models, transforms, stability, feedback, system response, control, time

  12. Vibration Analysis of Composite Beams with Sinusoidal Periodically Varying Interfaces

    Science.gov (United States)

    Li, Botong; Liu, Chein-Shan; Zhu, Liangliang

    2017-12-01

    As an increasing variety of composite materials with complex interfaces are emerging, we develop a theory to investigate composite beams and shed some light on new physical insights into composite beams with sinusoidal periodically varying interfaces. For the natural vibration of composite beams with continuous or periodically varying interfaces, the governing equation has been derived according to the generalised Hamiltonian principle. For composite beams having different boundary conditions, we transform the governing equations into integral equations and solve them by using the sinusoidal functions as test functions as well as the basis of the vibration modes. Due to the orthogonality of the sinusoidal functions, expansion coefficients in closed form can be found. Therefore, the proposed iterative schemes, with the help of the Rayleigh quotient and boundary functions, can quickly find the eigenvalues and free vibration modes. The obtained natural frequencies agree well with those obtained using the finite element method. In addition, the proposed method can be extended easily to laminated composite beams in more general cases or complex components and geometries in vibration engineering. The effects of different material properties of the upper and lower components and varying interface geometry function on the frequency of the composite beams are examined. According to our investigation, the natural frequency of a laminated beam with a continuous or periodically varying interface can be changed by altering the density or elastic modulus. We also show the responses of the frequencies of the components to the varying periodic interface.

  13. Time-varying Reeb Graphs: A Topological Framework Supporting the Analysis of Continuous Time-varying Data

    Energy Technology Data Exchange (ETDEWEB)

    Mascarenhas, Ajith Arthur [Univ. of North Carolina, Chapel Hill, NC (United States)

    2006-01-01

    I present time-varying Reeb graphs as a topological framework to support the analysis of continuous time-varying data. Such data is captured in many studies, including computational fluid dynamics, oceanography, medical imaging, and climate modeling, by measuring physical processes over time, or by modeling and simulating them on a computer. Analysis tools are applied to these data sets by scientists and engineers who seek to understand the underlying physical processes. A popular tool for analyzing scientific datasets is level sets, which are the points in space with a fixed data value s. Displaying level sets allows the user to study their geometry, their topological features such as connected components, handles, and voids, and to study the evolution of these features for varying s. For static data, the Reeb graph encodes the evolution of topological features and compactly represents topological information of all level sets. The Reeb graph essentially contracts each level set component to a point. It can be computed efficiently, and it has several uses: as a succinct summary of the data, as an interface to select meaningful level sets, as a data structure to accelerate level set extraction, and as a guide to remove noise. I extend these uses of Reeb graphs to time-varying data. I characterize the changes to Reeb graphs over time, and develop an algorithm that can maintain a Reeb graph data structure by tracking these changes over time. I store this sequence of Reeb graphs compactly, and call it a time-varying Reeb graph. I augment the time-varying Reeb graph with information that records the topology of level sets of all level values at all times, that maintains the correspondence of level set components over time, and that accelerates the extraction of level sets for a chosen level value and time. Scientific data sampled in space-time must be extended everywhere in this domain using an interpolant. A poor choice of interpolant can create degeneracies that are

  14. A dynamical model for generating synthetic Phonocardiogram signals.

    Science.gov (United States)

    Almasi, Ali; Shamsollahi, Mohammad B; Senhadji, Lotfi

    2011-01-01

    In this paper we introduce a dynamical model for Phonocardiogram (PCG) signal which is capable of generating realistic synthetic PCG signals. This model is based on PCG morphology and consists of three ordinary differential equations and can represent various morphologies of normal PCG signals. Beat-to-beat variation in PCG morphology is significant so model parameters vary from beat to beat. This model is inspired of Electrocardiogram (ECG) dynamical model proposed by McSharry et al. and can be employed to assess biomedical signal processing techniques.

  15. Robust linear parameter varying induction motor control with polytopic models

    Directory of Open Access Journals (Sweden)

    Dalila Khamari

    2013-01-01

    Full Text Available This paper deals with a robust controller for an induction motor which is represented as a linear parameter varying systems. To do so linear matrix inequality (LMI based approach and robust Lyapunov feedback controller are associated. This new approach is related to the fact that the synthesis of a linear parameter varying (LPV feedback controller for the inner loop take into account rotor resistance and mechanical speed as varying parameter. An LPV flux observer is also synthesized to estimate rotor flux providing reference to cited above regulator. The induction motor is described as a polytopic model because of speed and rotor resistance affine dependence their values can be estimated on line during systems operations. The simulation results are presented to confirm the effectiveness of the proposed approach where robustness stability and high performances have been achieved over the entire operating range of the induction motor.

  16. Altered Expression of Genes in Signaling Pathways Regulating Proliferation of Hematopoietic Stem and Progenitor Cells in Mice with Subchronic Benzene Exposure.

    Science.gov (United States)

    Sun, Rongli; Zhang, Juan; Xiong, Mengzhen; Wei, Haiyan; Tan, Kehong; Yin, Lihong; Pu, Yuepu

    2015-08-07

    Leukemias and hematopoietic disorders induced by benzene may arise from the toxicity of benzene to hematopoietic stem or progenitor cells (HS/PCs). Since there is a latency period between initial benzene exposure and the development of leukemia, subsequent impact of benzene on HS/PCs are crucial for a deeper understanding of the carcinogenicity and hematotoxicity in post-exposure stage. This study aims to explore the effects of benzene on HS/PCs and gene-expression in Wnt, Notch and Hh signaling pathways in post-exposure stage. The C3H/He mice were injected subcutaneously with benzene (0, 150, 300 mg/kg/day) for three months and were monitored for another 10 months post-exposure. The body weights were monitored, the relative organ weights, blood parameters and bone marrow smears were examined. Frequency of lineage(-) sca-1(+) c-kit(+) (LSK) cells, capability of colony forming and expression of genes in Wnt, Notch and Hedghog (Hh) signaling pathways were also analyzed. The colony formation of the progenitor cells for BFU-E, CFU-GEMM and CFU-GM was significantly decreased with increasing benzene exposure relative to controls, while no significant difference was observed in colonies for CFU-G and CFU-M. The mRNA level of cyclin D1 was increased and Notch 1 and p53 were decreased in LSK cells in mice exposed to benzene but with no statistical significance. These results suggest that subsequent toxic effects of benzene on LSK cells and gene expression in Wnt, Notch and Hh signaling pathways persist in post-exposure stage and may play roles in benzene-induced hematotoxicity.

  17. Epidermal growth factor-like domain 7 promotes migration and invasion of human trophoblast cells through activation of MAPK, PI3K and NOTCH signaling pathways.

    Science.gov (United States)

    Massimiani, M; Vecchione, L; Piccirilli, D; Spitalieri, P; Amati, F; Salvi, S; Ferrazzani, S; Stuhlmann, H; Campagnolo, L

    2015-05-01

    Epidermal growth factor-like domain 7 (Egfl7) is a gene that encodes a partially secreted protein and whose expression is largely restricted to the endothelia. We recently reported that EGFL7 is also expressed by trophoblast cells in mouse and human placentas. Here, we investigated the molecular pathways that are regulated by EGFL7 in trophoblast cells. Stable EGFL7 overexpression in a Jeg3 human choriocarcinoma cell line resulted in significantly increased cell migration and invasiveness, while cell proliferation was unaffected. Analysis of mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K) pathways showed that EGFL7 promotes Jeg3 cell motility by activating both pathways. We show that EGFL7 activates the epidermal growth factor receptor (EGFR) in Jeg3 cells, resulting in downstream activation of extracellular regulated kinases (ERKs). In addition, we provide evidence that EGFL7-triggered migration of Jeg3 cells involves activation of NOTCH signaling. EGFL7 and NOTCH1 are co-expressed in Jeg3 cells, and blocking of NOTCH activation abrogates enhanced migration of Jeg3 cells overexpressing EGFL7. We also demonstrate that signaling through EGFR and NOTCH converged to mediate EGFL7 effects. Reduction of endogenous EGFL7 expression in Jeg3 cells significantly decreased cell migration. We further confirmed that EGFL7 stimulates cell migration by using primary human first trimester trophoblast (PTB) cells overexpressing EGFL7. In conclusion, our data suggest that in trophoblast cells, EGFL7 regulates cell migration and invasion by activating multiple signaling pathways. Our results provide a possible explanation for the correlation between reduced expression of EGFL7 and inadequate trophoblast invasion observed in placentopathies. © The Author 2015. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  18. Precoder and decoder prediction in time-varying MIMO channel

    DEFF Research Database (Denmark)

    Nguyen, Tuan Hung; Leus, Geert; Khaled, Nadia

    2005-01-01

    In mobile communications, time varying channels make the available channel information out of date. Timely updating the channel state is an obvious solution to improve the system performance in a time varying channel. However, a better knowledge of the channel comes at the cost of a decrease...... in the system throughput. Thus, predicting the future channel conditions can improve not only the performance but also the throughput of many types of wireless systems. This is especially true for a wireless system where multiple antennas are applied at both link ends. In this report we propose and evaluate...

  19. Partially linear varying coefficient models stratified by a functional covariate

    KAUST Repository

    Maity, Arnab

    2012-10-01

    We consider the problem of estimation in semiparametric varying coefficient models where the covariate modifying the varying coefficients is functional and is modeled nonparametrically. We develop a kernel-based estimator of the nonparametric component and a profiling estimator of the parametric component of the model and derive their asymptotic properties. Specifically, we show the consistency of the nonparametric functional estimates and derive the asymptotic expansion of the estimates of the parametric component. We illustrate the performance of our methodology using a simulation study and a real data application.

  20. Dietary adaptation of FADS genes in Europe varied across time and geography.

    Science.gov (United States)

    Ye, Kaixiong; Gao, Feng; Wang, David; Bar-Yosef, Ofer; Keinan, Alon

    2017-05-26

    Fatty acid desaturase (FADS) genes encode rate-limiting enzymes for the biosynthesis of omega-6 and omega-3 long-chain polyunsaturated fatty acids (LCPUFAs). This biosynthesis is essential for individuals subsisting on LCPUFA-poor diets (for example, plant-based). Positive selection on FADS genes has been reported in multiple populations, but its cause and pattern in Europeans remain unknown. Here we demonstrate, using ancient and modern DNA, that positive selection acted on the same FADS variants both before and after the advent of farming in Europe, but on opposite (that is, alternative) alleles. Recent selection in farmers also varied geographically, with the strongest signal in southern Europe. These varying selection patterns concur with anthropological evidence of varying diets, and with the association of farming-adaptive alleles with higher FADS1 expression and thus enhanced LCPUFA biosynthesis. Genome-wide association studies reveal that farming-adaptive alleles not only increase LCPUFAs, but also affect other lipid levels and protect against several inflammatory diseases.

  1. Time-invariant measurement of time-varying bioimpedance using vector impedance analysis.

    Science.gov (United States)

    Sanchez, B; Louarroudi, E; Pintelon, R

    2015-03-01

    When stepped-sine impedance spectroscopy measurements are carried out on (periodically) time-varying bio-systems, the inherent time-variant (time-periodic) parts are traditionally ignored or mitigated by filtering. The latter, however, lacks theoretical foundation and, in this paper, it is shown that it only works under certain specific conditions. Besides, we propose an alternative method, based on multisine signals, that exploits the non-stationary nature in time-varying bio-systems with a dominant periodic character, such as cardiovascular and respiratory systems, or measurements interfered with by their physiological activities. The novel method extracts the best—in a mean square sense—linear time-invariant (BLTI) impedance approximation ZBLTI(jω) of a periodically time-varying (PTV) impedance ZPTV(jω, t) as well as its time-periodic part. Relying on the geometrical interpretation of the BLTI concept, a new impedance analysis tool, called vector impedance analysis (VIA), is also presented. The theoretical and practical aspects are validated through measurements performed on a PTV dummy circuit and on an in vivo myocardial tissue.

  2. Signal sampling circuit

    NARCIS (Netherlands)

    Louwsma, S.M.; Vertregt, Maarten

    2011-01-01

    A sampling circuit for sampling a signal is disclosed. The sampling circuit comprises a plurality of sampling channels adapted to sample the signal in time-multiplexed fashion, each sampling channel comprising a respective track-and-hold circuit connected to a respective analogue to digital

  3. Signal sampling circuit

    NARCIS (Netherlands)

    Louwsma, S.M.; Vertregt, Maarten

    2010-01-01

    A sampling circuit for sampling a signal is disclosed. The sampling circuit comprises a plurality of sampling channels adapted to sample the signal in time-multiplexed fashion, each sampling channel comprising a respective track-and-hold circuit connected to a respective analogue to digital

  4. Ubiquitination in apoptosis signaling

    NARCIS (Netherlands)

    van de Kooij, L.W.

    2014-01-01

    The work described in this thesis focuses on ubiquitination and protein degradation, with an emphasis on how these processes regulate apoptosis signaling. More specifically, our aims were: 1. To increase the understanding of ubiquitin-mediated regulation of apoptosis signaling. 2. To identify the E3

  5. SignalR blueprints

    CERN Document Server

    Ingebrigtsen, Einar

    2015-01-01

    This book is designed for software developers, primarily those with knowledge of C#, .NET, and JavaScript. Good knowledge and understanding of SignalR is assumed to allow efficient programming of core elements and applications in SignalR.

  6. Optimal fault signal estimation

    NARCIS (Netherlands)

    Stoorvogel, Antonie Arij; Niemann, H.H.; Saberi, A.; Sannuti, P.

    2002-01-01

    We consider here both fault identification and fault signal estimation. Regarding fault identification, we seek either exact or almost fault identification. On the other hand, regarding fault signal estimation, we seek either $H_2$ optimal, $H_2$ suboptimal or Hinfinity suboptimal estimation. By

  7. Multiresolution signal decomposition schemes

    NARCIS (Netherlands)

    J. Goutsias (John); H.J.A.M. Heijmans (Henk)

    1998-01-01

    textabstract[PNA-R9810] Interest in multiresolution techniques for signal processing and analysis is increasing steadily. An important instance of such a technique is the so-called pyramid decomposition scheme. This report proposes a general axiomatic pyramid decomposition scheme for signal analysis

  8. Dose-to-duration encoding and signaling beyond saturation in intracellular signaling networks.

    Directory of Open Access Journals (Sweden)

    Marcelo Behar

    2008-10-01

    Full Text Available The cellular response elicited by an environmental cue typically varies with the strength of the stimulus. For example, in the yeast Saccharomyces cerevisiae, the concentration of mating pheromone determines whether cells undergo vegetative growth, chemotropic growth, or mating. This implies that the signaling pathways responsible for detecting the stimulus and initiating a response must transmit quantitative information about the intensity of the signal. Our previous experimental results suggest that yeast encode pheromone concentration as the duration of the transmitted signal. Here we use mathematical modeling to analyze possible biochemical mechanisms for performing this "dose-to-duration" conversion. We demonstrate that modulation of signal duration increases the range of stimulus concentrations for which dose-dependent responses are possible; this increased dynamic range produces the counterintuitive result of "signaling beyond saturation" in which dose-dependent responses are still possible after apparent saturation of the receptors. We propose a mechanism for dose-to-duration encoding in the yeast pheromone pathway that is consistent with current experimental observations. Most previous investigations of information processing by signaling pathways have focused on amplitude encoding without considering temporal aspects of signal transduction. Here we demonstrate that dose-to-duration encoding provides cells with an alternative mechanism for processing and transmitting quantitative information about their surrounding environment. The ability of signaling pathways to convert stimulus strength into signal duration results directly from the nonlinear nature of these systems and emphasizes the importance of considering the dynamic properties of signaling pathways when characterizing their behavior. Understanding how signaling pathways encode and transmit quantitative information about the external environment will not only deepen our

  9. Signals and transforms in linear systems analysis

    CERN Document Server

    Wasylkiwskyj, Wasyl

    2013-01-01

    Signals and Transforms in Linear Systems Analysis covers the subject of signals and transforms, particularly in the context of linear systems theory. Chapter 2 provides the theoretical background for the remainder of the text. Chapter 3 treats Fourier series and integrals. Particular attention is paid to convergence properties at step discontinuities. This includes the Gibbs phenomenon and its amelioration via the Fejer summation techniques. Special topics include modulation and analytic signal representation, Fourier transforms and analytic function theory, time-frequency analysis and frequency dispersion. Fundamentals of linear system theory for LTI analogue systems, with a brief account of time-varying systems, are covered in Chapter 4 . Discrete systems are covered in Chapters 6 and 7.  The Laplace transform treatment in Chapter 5 relies heavily on analytic function theory as does Chapter 8 on Z -transforms. The necessary background on complex variables is provided in Appendix A. This book is intended to...

  10. Neutron signal transfer analysis

    CERN Document Server

    Pleinert, H; Lehmann, E

    1999-01-01

    A new method called neutron signal transfer analysis has been developed for quantitative determination of hydrogenous distributions from neutron radiographic measurements. The technique is based on a model which describes the detector signal obtained in the measurement as a result of the action of three different mechanisms expressed by signal transfer functions. The explicit forms of the signal transfer functions are determined by Monte Carlo computer simulations and contain only the distribution as a variable. Therefore an unknown distribution can be determined from the detector signal by recursive iteration. This technique provides a simple and efficient tool for analysis of this type while also taking into account complex effects due to the energy dependency of neutron interaction and single and multiple scattering. Therefore this method provides an efficient tool for precise quantitative analysis using neutron radiography, as for example quantitative determination of moisture distributions in porous buil...

  11. Molecular and Cellular Signaling

    CERN Document Server

    Beckerman, Martin

    2005-01-01

    A small number of signaling pathways, no more than a dozen or so, form a control layer that is responsible for all signaling in and between cells of the human body. The signaling proteins belonging to the control layer determine what kinds of cells are made during development and how they function during adult life. Malfunctions in the proteins belonging to the control layer are responsible for a host of human diseases ranging from neurological disorders to cancers. Most drugs target components in the control layer, and difficulties in drug design are intimately related to the architecture of the control layer. Molecular and Cellular Signaling provides an introduction to molecular and cellular signaling in biological systems with an emphasis on the underlying physical principles. The text is aimed at upper-level undergraduates, graduate students and individuals in medicine and pharmacology interested in broadening their understanding of how cells regulate and coordinate their core activities and how diseases ...

  12. HES1, a target of Notch signaling, is elevated in canine osteosarcoma, but reduced in the most aggressive tumors.

    Science.gov (United States)

    Dailey, Deanna D; Anfinsen, Kristin P; Pfaff, Liza E; Ehrhart, E J; Charles, J Brad; Bønsdorff, Tina B; Thamm, Douglas H; Powers, Barbara E; Jonasdottir, Thora J; Duval, Dawn L

    2013-07-01

    Hairy and enhancer of split 1 (HES1), a basic helix-loop-helix transcriptional repressor, is a downstream target of Notch signaling. Notch signaling and HES1 expression have been linked to growth and survival in a variety of human cancer types and have been associated with increased metastasis and invasiveness in human osteosarcoma cell lines. Osteosarcoma (OSA) is an aggressive cancer demonstrating both high metastatic rate and chemotherapeutic resistance. The current study examined expression of Notch signaling mediators in primary canine OSA tumors and canine and human osteosarcoma cell lines to assess their role in OSA development and progression. Reverse transcriptase - quantitative PCR (RT-qPCR) was utilized to quantify HES1, HEY1, NOTCH1 and NOTCH2 gene expression in matched tumor and normal metaphyseal bone samples taken from dogs treated for appendicular OSA at the Colorado State University Veterinary Teaching Hospital. Gene expression was also assessed in tumors from dogs with a disease free interval (DFI) of  300 days following treatment with surgical amputation followed by standard chemotherapy. Immunohistochemistry was performed to confirm expression of HES1. Data from RT-qPCR and immunohistochemical (IHC) experiments were analyzed using REST2009 software and survival analysis based on IHC expression employed the Kaplan-Meier method and log rank analysis. Unbiased clustered images were generated from gene array analysis data for Notch/HES1 associated genes. Gene array analysis of Notch/HES1 associated genes suggested alterations in the Notch signaling pathway may contribute to the development of canine OSA. HES1 mRNA expression was elevated in tumor samples relative to normal bone, but decreased in tumor samples from dogs with a DFI 300 days. NOTCH2 and HEY1 mRNA expression was also elevated in tumors relative to normal bone, but was not differentially expressed between the DFI tumor groups. Survival analysis confirmed an association between

  13. Computation of gradually varied flow in compound open channel ...

    Indian Academy of Sciences (India)

    In this method, the energy and continuity equations are solved for steady, gradually varied flow by the Newton–Raphson method and the proposed methodology is applied to tree-type and looped-channel networks. An algorithm is presented to determine multiple critical depths in a compound channel. Modifications in ...

  14. Time Varying Market Integration and Expected Rteurns in Emerging Markets

    NARCIS (Netherlands)

    de Jong, F.C.J.M.; de Roon, F.A.

    2001-01-01

    We use a simple model in which the expected returns in emerging markets depend on their systematic risk as measured by their beta relative to the world portfolio as well as on the level of integration in that market.The level of integration is a time-varying variable that depends on the market value

  15. Overcoming Spurious Regression Using time-Varying Fourier ...

    African Journals Online (AJOL)

    Non-stationary time series data have been traditionally analyzed in the frequency domain by assuming constant amplitudes regardless of the timelag. A new approach called time-varying amplitude method (TVAM) is presented here. Oscillations are analyzed for changes in the magnitude of Fourier Coefficients which are ...

  16. Multivariate Option Pricing with Time Varying Volatility and Correlations

    DEFF Research Database (Denmark)

    Rombouts, Jeroen V.K.; Stentoft, Lars Peter

    In recent years multivariate models for asset returns have received much attention, in particular this is the case for models with time varying volatility. In this paper we consider models of this class and examine their potential when it comes to option pricing. Specifically, we derive the risk ...

  17. Microwave oven-induced decalcification at varying temperatures: A ...

    African Journals Online (AJOL)

    This study was designed to evaluate the effect of decalcifying fluid types on bone tissue architecture and its staining properties following decalcification at varying temperatures. A decalcification methodology using Golding and Stewards (GS) fluid, and Jenkings fluid (JK), and a modern household microwave oven to ...

  18. A five-dimensional model of varying fine structure constant

    Indian Academy of Sciences (India)

    A five-dimensional model of varying fine structure constant. J P MBELEK. Service d'Astrophysique, C.E. Saclay, F-91191 Gif-sur-Yvette Cedex, France. Abstract. The cosmological variation of the fine structure constant « is explored from an effective theory, under the form of an improved version of the 5D Kaluza-Klein theory.

  19. A five-dimensional model of varying fine structure constant

    Indian Academy of Sciences (India)

    dimensional model of varying fine structure constant. J P Mbelek. Cosmology Volume 62 Issue 3 March 2004 pp 741-743. Fulltext. Click here to view fulltext PDF. Permanent link: http://www.ias.ac.in/article/fulltext/pram/062/03/0741-0743 ...

  20. Incremental Closed-loop Identification of Linear Parameter Varying Systems

    DEFF Research Database (Denmark)

    Bendtsen, Jan Dimon; Trangbæk, Klaus

    2011-01-01

    This paper deals with system identification for control of linear parameter varying systems. In practical applications, it is often important to be able to identify small plant changes in an incremental manner without shutting down the system and/or disconnecting the controller; unfortunately, cl...

  1. Effects of varying protein levels on broiler performance when dietary ...

    African Journals Online (AJOL)

    Effects of varying protein levels on broiler performance when dietary energy levels remain constant. S A Osei, K Effah-Baah. Abstract. (Ghana Journal of Agricultural Science, 1987-90, 20-23: 21-24). Full Text: EMAIL FULL TEXT EMAIL FULL TEXT · DOWNLOAD FULL TEXT DOWNLOAD FULL TEXT · AJOL African Journals ...

  2. Adolescent Sexual Behaviors at Varying Levels of Substance Use Frequency

    Science.gov (United States)

    Floyd, Leah J.; Latimer, William

    2010-01-01

    Combining substance use and sex compounds the risk of contracting sexually transmitted diseases, including HIV. However, the association between substance use and sexual behaviors may vary by substance and sexual behavior. The current study sought to examine the relationship between alcohol and marijuana use frequency and specific sexual…

  3. Response of Japanese Breeder Quails to Varying Dietary Protein ...

    African Journals Online (AJOL)

    A three months feeding trial was conducted to assess the effects of feeding varying levels of dietary protein on productive performance, egg quality characteristics and hatchability using 930 six weeks breeders quails. The birds were randomly divided into five dietary treatment groups of 186 birds, and were further replicated ...

  4. Performance and cost implication of finisher turkeys fed varying ...

    African Journals Online (AJOL)

    A 28-day experiment was conducted to determine the effect of feeding varying levels of rice milling waste as a substitute on maize on the performance, nutrient utilization and the economics implication on finisher turkeys. Five turkey finisher diets were formulated by substituting maize with rice milling waste at 0%, 25%, 50%, ...

  5. Effect of Varying Concentration of Auxins and Stem Length on ...

    African Journals Online (AJOL)

    A study was carried out to evaluate the effect of varying hormonal treatments and length of cuttings of clonal materials on the sprouting and rooting abilities of Jatropha curcas L. Two stem cutting lengths: 30cm and 60cm were pre-treated with two types of auxins: Naphthalene Acetic Acid (NAA) and Indole-3-Butyric Acid ...

  6. Non-stationary vibrations of mechanical systems with slowly varying ...

    African Journals Online (AJOL)

    The paper presents an approximate analytical solution for investigation of vibration responses in linear Single-Degree-of-Freedom-Systems (SDOF) with slowly varying natural frequency subjected to a transient excitalion force with constant amplitude. The solution employs the WBKJ-approximation method, the method of ...

  7. Explicit Analytical Solution of a Pendulum with Periodically Varying Length

    Science.gov (United States)

    Yang, Tianzhi; Fang, Bo; Li, Song; Huang, Wenhu

    2010-01-01

    A pendulum with periodically varying length is an interesting physical system. It has been studied by some researchers using traditional perturbation methods (for example, the averaging method). But due to the limitation of the conventional perturbation methods, the solutions are not valid for long-term prediction of the pendulum. In this paper,…

  8. SANS investigation on evolution of pore morphology for varying ...

    Indian Academy of Sciences (India)

    morphology for varying sintering time in porous ceria. A K PATRA1, S RAMANATHAN2, D SEN1 and S MAZUMDER1. 1Solid State Physics Division; 2Materials Science Division, Bhabha Atomic Research. Centre, Mumbai 400 085, India. E-mail: apatra@magnum.barc.ernet.in. Abstract. Precipitates of ceria were synthesized ...

  9. Time-varying correlation and common structures in volatility

    NARCIS (Netherlands)

    Liu, Yang

    2016-01-01

    This thesis studies time series properties of the covariance structure of multivariate asset returns. First, the time-varying feature of correlation is investigated at the intraday level with a new correlation model incorporating the intraday correlation dynamics. Second, the thesis develops a

  10. Crop-Livestock Farming Systems Varying with Different Altitudes in ...

    African Journals Online (AJOL)

    In Sub-Saharan Africa, rangeland is increasingly converted to cropland, creating diverse crop-livestock practices in different environments. As these practices lead to highly adapted livestock production systems using resources that vary locally and seasonally, not much is known about their similarities and differences.

  11. Time-varying Combinations of Predictive Densities using Nonlinear Filtering

    NARCIS (Netherlands)

    M. Billio (Monica); R. Casarin (Roberto); F. Ravazzolo (Francesco); H.K. van Dijk (Herman)

    2012-01-01

    textabstractWe propose a Bayesian combination approach for multivariate predictive densities which relies upon a distributional state space representation of the combination weights. Several specifications of multivariate time-varying weights are introduced with a particular focus on weight dynamics

  12. The Multi-Vari Chart -- A Systematic Approach

    NARCIS (Netherlands)

    de Mast, J.; Roes, K.C.B.; Does, R.J.M.M.

    1999-01-01

    Prior to setting up a designed experiment or setting up a monitoring system for a process most experimenters perform an exploratory study to investigate thestructure of the process' variation. Tools that are frequently used for such a study are predominantly graphical in nature.The multi-vari chart

  13. Sheep response to sugar cane tops supplemented with varying ...

    African Journals Online (AJOL)

    This study was conducted to examine the response of West African Dwarf (WAD) sheep to sugarcane (Sacccharum officinarum) tops supplemented with varying levels of Leucaena leucocephala foliage. Twenty WAD sheep averaging 10.14kg were randomly divided into four groups of 5 replicates, and each group was fed ...

  14. Estimation of time-varying channels - A block approach

    NARCIS (Netherlands)

    Leus, G.; Tang, Z.; Banelli, P.

    2011-01-01

    Channel state information (CSI) is indispensable for coherent detection in a wireless communication system. The pilot-aided method is one of the most intensively studied approaches for channel estimation. This method is especially attractive for time-varying channels because of their short coherence

  15. Artificial Bee Colony Algorithm with Time-Varying Strategy

    Directory of Open Access Journals (Sweden)

    Quande Qin

    2015-01-01

    Full Text Available Artificial bee colony (ABC is one of the newest additions to the class of swarm intelligence. ABC algorithm has been shown to be competitive with some other population-based algorithms. However, there is still an insufficiency that ABC is good at exploration but poor at exploitation. To make a proper balance between these two conflictive factors, this paper proposed a novel ABC variant with a time-varying strategy where the ratio between the number of employed bees and the number of onlooker bees varies with time. The linear and nonlinear time-varying strategies can be incorporated into the basic ABC algorithm, yielding ABC-LTVS and ABC-NTVS algorithms, respectively. The effects of the added parameters in the two new ABC algorithms are also studied through solving some representative benchmark functions. The proposed ABC algorithm is a simple and easy modification to the structure of the basic ABC algorithm. Moreover, the proposed approach is general and can be incorporated in other ABC variants. A set of 21 benchmark functions in 30 and 50 dimensions are utilized in the experimental studies. The experimental results show the effectiveness of the proposed time-varying strategy.

  16. Response of rabbits to varying levels of cassava and Leucaena ...

    African Journals Online (AJOL)

    An experiment was carried out to determine the performance, haematology, carcass characteristics and sensory evaluation of meat from rabbits (n = 30) fed varying levels of cassava and Leucaena leaf meal diets. Rabbits were randomly allocated to five dietary treatments of 0, 10, 20, 30 and 40% CLM replaced with LLM for ...

  17. Water use efficiency of six rangeland grasses under varied soil ...

    African Journals Online (AJOL)

    The changes in soil moisture content were measured by Gypsum Block which aided in determining the irrigation schedules. The grasses demonstrated varied levels of WUE which was evaluated by amount of biomass productivity in relation to evapotranspired water during the growing period. The three soil moisture content ...

  18. Performance and External Egg Quality of Layers under Varying ...

    African Journals Online (AJOL)

    Performance and External Egg Quality of Layers under Varying Stocking ... Study determined the performance and external egg quality of layers in locally fabricated metal-type battery cage at different stocking density. ... Birds stocked at 2/cell gained 15g/birds in weight while birds stocked 3 and 4 ... OTHER RESOURCES.

  19. Electricity Futures Prices : Time Varying Sensitivity to Fundamentals

    NARCIS (Netherlands)

    S-E. Fleten (Stein-Erik); R. Huisman (Ronald); M. Kilic (Mehtap); H.P.G. Pennings (Enrico); S. Westgaard (Sjur)

    2014-01-01

    textabstractThis paper provides insight in the time-varying relation between electricity futures prices and fundamentals in the form of prices of contracts for fossil fuels. As supply curves are not constant and different producers have different marginal costs of production, we argue that the

  20. Mining Graphs for Understanding Time-Varying Volumetric Data.

    Science.gov (United States)

    Gu, Yi; Wang, Chaoli; Peterka, Tom; Jacob, Robert; Kim, Seung Hyun

    2016-01-01

    A notable recent trend in time-varying volumetric data analysis and visualization is to extract data relationships and represent them in a low-dimensional abstract graph view for visual understanding and making connections to the underlying data. Nevertheless, the ever-growing size and complexity of data demands novel techniques that go beyond standard brushing and linking to allow significant reduction of cognition overhead and interaction cost. In this paper, we present a mining approach that automatically extracts meaningful features from a graph-based representation for exploring time-varying volumetric data. This is achieved through the utilization of a series of graph analysis techniques including graph simplification, community detection, and visual recommendation. We investigate the most important transition relationships for time-varying data and evaluate our solution with several time-varying data sets of different sizes and characteristics. For gaining insights from the data, we show that our solution is more efficient and effective than simply asking users to extract relationships via standard interaction techniques, especially when the data set is large and the relationships are complex. We also collect expert feedback to confirm the usefulness of our approach.

  1. Modelling Acoustic Wave Propagation in Axisymmetric Varying-Radius Waveguides

    DEFF Research Database (Denmark)

    Bæk, David; Willatzen, Morten

    2008-01-01

    A computationally fast and accurate model (a set of coupled ordinary differential equations) for fluid sound-wave propagation in infinite axisymmetric waveguides of varying radius is proposed. The model accounts for fluid heat conduction and fluid irrotational viscosity. The model problem is solved...

  2. Effects of varying dietary zinc levels on energy and nitrogen ...

    African Journals Online (AJOL)

    Effects of varying dietary zinc levels on energy and nitrogen utilization in West African dwarf kids. ... Animals were transferred to individual metabolic cages for separate collection of feaces and urine 14 and 15 weeks later. Parameters determined were dry matter intake (DMI), energy utilization and nitrogen utilization.

  3. The Mathematics of Ghanaian circular musical drumheads: varying ...

    African Journals Online (AJOL)

    In this work the drumhead is modeled, by making the tension in it to vary as a periodic function of time, using the two dimensional wave equation. The separated Ordinary Differential Equations (ODEs) are solved and the Fourier- Bessel coefficients are determined using the initial and boundary conditions imposed on the ...

  4. Effects Of Varying Levels Of Dietary Protein On The Carcass ...

    African Journals Online (AJOL)

    Sixteen New Zealand White rabbits aged 9-10 weeks and weighing 0.72-0.99 kg were used to examine the effects of varying levels of dietary protein on carcass characteristics of rabbits. They were divided into four groups and allotted to four dietary treatments A, B, C and D formulated with 10, 13, 16 and 20 % crude protein ...

  5. with varying Levels of Moringa oleifera Leaves Powder

    African Journals Online (AJOL)

    The study was conducted to evaluate the organoleptic properties of soy meatball at varying levels of Moringa oleifera leaves powder inclusion. The result of the sensory evaluation of the products showed that they were generally accepted above average (3.5). However, soy meatball sample without Moringa oleifera leaves ...

  6. Peer influence on school learning among students of varying socio ...

    African Journals Online (AJOL)

    This study examined peer Influence on School Learning among students of varying socio-economic backgrounds. One hundred and twenty students (60 males and 60 females) with a mean age 15.1 years were randomly selected from four co-educational Secondary Schools in Ikenne Local Government area of Ogun State.

  7. Time varying market efficiency of the GCC stock markets

    Science.gov (United States)

    Charfeddine, Lanouar; Khediri, Karim Ben

    2016-02-01

    This paper investigates the time-varying levels of weak-form market efficiency for the GCC stock markets over the period spanning from May 2005 to September 2013. We use two empirical approaches: (1) the generalized autoregressive conditional heteroscedasticity in mean (GARCH-M) model with state space time varying parameter (Kalman filter), and (2) a rolling technique sample test of the fractional long memory parameter d. As long memory estimation methods, we use the detrended fluctuation analysis (DFA) technique, the modified R/S statistic, the exact local whittle (ELW) and the feasible Exact Local Whittle (FELW) methods. Moreover, we use the Bai and Perron (1998, 2003) multiple structural breaks technique to test and date the time varying behavior of stock market efficiency. Empirical results show that GCC markets have different degrees of time-varying efficiency, and also have experiencing periods of efficiency improvement. Results also show evidence of structural breaks in all GCC markets. Moreover, we observe that the recent financial shocks such as Arab spring and subprime crises have a significant impact on the time path evolution of market efficiency.

  8. Weakly Nonlinear Waves with Slowly-Varying Speed | Chikwendu ...

    African Journals Online (AJOL)

    A previously developed method of generating uniformly valid, multiple- scale asymptotic expansions for the solution of weakly nonlinear one-dimensional wave equations is applied to problems with slowly-varying speed. The method is also shown to be applicable specifically to periodic initial data.

  9. Karlovy Varys linastub kaks Eesti filmi / Andris Feldmanis

    Index Scriptorium Estoniae

    Feldmanis, Andris, 1982-

    2007-01-01

    Ilmar Raagi mängufilm "Klass" osaleb 42. Karlovy Vary rahvusvahelise filmifestivali võistlusprogrammis "East of the West" ja Asko Kase lühimängufilm "Zen läbi prügi" on valitud festivali kõrvalprogrammi "Forum of Independents"

  10. 570 comparative evaluation of concrete properties with varying

    African Journals Online (AJOL)

    Osondu

    2013-09-03

    Sep 3, 2013 ... Periwinkle shell ash; Varying proportions. Introduction. Building construction works and Civil. Engineering practice in Nigeria depend, to a very large extent, on concrete as major construction material. The versatility, strength and durability of cement are of utmost priority over other construction materials.

  11. Effect of varying concentrations of orally ingested glucose on platelet ...

    African Journals Online (AJOL)

    The physiologic basis of bleeding is a function of normal platelets and coagulation factors. This study is aimed at ascertaining the effect of varying concentrations of orally ingested glucose on platelet count and hemoglobin concentration during menstruation. Forty menstruating students between the ages of 18 and 25 from ...

  12. Modelling Flow over Stepped Spillway with Varying Chute Geometry ...

    African Journals Online (AJOL)

    This study has modeled some characteristics of the flows over stepped spillway with varying chute geometry through a laboratory investigation. Using six physically built stepped spillway models, with each having six horizontal plain steps at 4cm constant height, 30 cm width and respective chute slope angles at 310, 320, ...

  13. Nonlinear MPC Design for Identified Nonlinear Parameter Varying (NPV Model

    Directory of Open Access Journals (Sweden)

    Jiangang Lu

    2012-09-01

    Full Text Available In this paper, a novel nonlinear model predictive controller (MPC is proposed based on an identified nonlinear parameter varying (NPV model. Firstly, an NPV model scheme is present for process identification, which is featured by its nonlinear hybrid Hammerstein model structure and varying model parameters. The hybrid Hammerstein model combines a normalized static artificial neural network with a linear transfer function to identify general nonlinear systems at each fixed working point. Meanwhile, a model interpolating philosophy is utilized to obtain the global model across the whole operation domain. The NPV model considers both the nonlinearity of transition dynamics due to the variation of the working-point and the nonlinear mapping from the input to the output at fixed working points. Moreover, under the new NPV framework, the control action is computed via a multistep linearization method aimed for nonlinear optimization problems. In the proposed scheme, only low cost tests are needed for system identification and the controller can achieve better output performance than MPC methods based on linear parameter varying (LPV models. Numerical examples validate the effectiveness of the proposed approach. Keywords: Nonlinear parameter varying (NPV, Hammerstein model, nonlinear MPC.

  14. Additional Surgery after Breast-Conserving Surgery Varies Widely

    Science.gov (United States)

    A study published in the Feb. 1, 2012, issue of JAMA found that the number of women who have one or more additional surgeries to remove suspected residual tumor tissue (re-excisions) following breast-conserving surgery (BCS) for breast cancer varies widely across surgeons and hospitals.

  15. Steady shear viscosity of stirred yoghurts with varying ropiness

    NARCIS (Netherlands)

    van Marle, M.E.; van Marle, M.E.; van den Ende, Henricus T.M.; de Kruif, C.G.; de Kruif, C.G.; Mellema, J.

    1999-01-01

    Stirred yogurt was viewed as a concentrated dispersion of aggregates consisting of protein particles. The steady-shear behavior of three types of stirred yogurt with varying ropiness was investigated experimentally. To describe the shear-dependent viscosity, a microrheological model was used which

  16. Effects of fertilizer types and varying population on the performance ...

    African Journals Online (AJOL)

    On the two-year averages,the significant percentage increases in the length of cocoyam cormel under fertilizer types were 67, 93 and 148% by inorganic, organic and inorganic + organic fertilizers, respectively. The significant percentage decreases in the length of cocoyam cormels under varying populations of 10,000, ...

  17. Nutrient Intake and Digestibility of Red Sokoto Bucks Fed Varying ...

    African Journals Online (AJOL)

    An experiment was conducted to evaluate dry matter intake, total tract digestibility and nitrogen balance by red Sokoto bucks fed varying levels of Gmelina arborea leaf meal (GLM). Diet 1 devoid of GLM served as the control. Diets 2, 3 and 4 had GLM supplemented at 10, 20, 30% levels, respectively. A 4X4 Latin square ...

  18. Reliability of Distribution Systems with Effect of Time-Varying-Repair Time and Time-Varying Weight Factors

    Science.gov (United States)

    Eshtehardiha, S.; Poudeh, M. Bayati

    2008-10-01

    Reliable evaluation of distribution systems is of high importance in the maintenance and expansion of these systems. A time-sequential simulation technique is presented in this paper in which the effects of weather conditions and maintenance methods in the assessment of reliable cost of integrated distribution systems are provided. Time-Varying Weight Factors (TVWF) are defined to investigate the effect of weather conditions and present maintenance methods on Failure rates (FR). In fact, the average Failure Rate (FR) is combined with TVWF to provide time-varying repair times (TVRT) for each component. Similarly, the average Repair Time (RT) is also combined with TVWF to produce Time-Varying-Repair Time (TVRT). An experimental distribution system showed that TVFR has more effects on the interruption costs of the sensitive costumers. It has also significant effects on the indices of all costumers. So, it is necessary to consider TVRT in evaluating the reliability of the network cost.

  19. Visualizing Time: How Linguistic Metaphors Are Incorporated into Displaying Instruments in the Process of Interpreting Time-Varying Signals

    Science.gov (United States)

    Garcia-Belmonte, Germà

    2017-01-01

    Spatial visualization is a well-established topic of education research that has allowed improving science and engineering students' skills on spatial relations. Connections have been established between visualization as a comprehension tool and instruction in several scientific fields. Learning about dynamic processes mainly relies upon static…

  20. Studies on sound signal scattering from varying seabed sediments of the western continental shelf of India: Cochin to Mangalore

    Digital Repository Service at National Institute of Oceanography (India)

    Chakraborty, B.; Pathak, D.

    ) of echo amplitude, root mean square (rmm) roughness of the seabed and coherent reflection coefficient at the water bottom interface show that the areas are generally smooth. A comparative study of the reflection coefficients computed from the ground truth...

  1. Simulated performance of an acoustic modem using phase-modulated signals in a time-varying, shallow-water environment

    DEFF Research Database (Denmark)

    Bjerrum-Niese, Christian; Jensen, Leif Bjørnø

    1996-01-01

    Underwater acoustic modems using coherent modulation, such as phase-shift keying, have proven to efficiently exploit the bandlimited underwater acoustical communication channel. However, the performance of an acoustic modem, given as maximum range and data and error rate, is limited in the complex...

  2. Ambulatory estimation of human circadian phase using models of varying complexity based on non-invasive signal modalities

    NARCIS (Netherlands)

    Gil, Enrique A; Aubert, Xavier L; Beersma, Domien G M

    In this work, we introduce a number of models for human circadian phase estimation in ambulatory conditions using various sensor modalities. Machine learning techniques have been applied to ambulatory recordings of wrist actigraphy, light exposure, electrocardiograms (ECG), and distal and proximal

  3. Vesicle biomechanics in a time-varying magnetic field.

    Science.gov (United States)

    Ye, Hui; Curcuru, Austen

    2015-01-01

    Cells exhibit distortion when exposed to a strong electric field, suggesting that the field imposes control over cellular biomechanics. Closed pure lipid bilayer membranes (vesicles) have been widely used for the experimental and theoretical studies of cellular biomechanics under this electrodeformation. An alternative method used to generate an electric field is by electromagnetic induction with a time-varying magnetic field. References reporting the magnetic control of cellular mechanics have recently emerged. However, theoretical analysis of the cellular mechanics under a time-varying magnetic field is inadequate. We developed an analytical theory to investigate the biomechanics of a modeled vesicle under a time-varying magnetic field. Following previous publications and to simplify the calculation, this model treated the inner and suspending media as lossy dielectrics, the membrane thickness set at zero, and the electric resistance of the membrane assumed to be negligible. This work provided the first analytical solutions for the surface charges, electric field, radial pressure, overall translational forces, and rotational torques introduced on a vesicle by the time-varying magnetic field. Frequency responses of these measures were analyzed, particularly the frequency used clinically by transcranial magnetic stimulation (TMS). The induced surface charges interacted with the electric field to produce a biomechanical impact upon the vesicle. The distribution of the induced surface charges depended on the orientation of the coil and field frequency. The densities of these charges were trivial at low frequency ranges, but significant at high frequency ranges. The direction of the radial force on the vesicle was dependent on the conductivity ratio between the vesicle and the medium. At relatively low frequencies (biomechanics under a time-varying magnetic field. Biological effects of clinical TMS are not likely to occur via alteration of the biomechanics of brain

  4. Neural coding of time-varying interaural time differences and time-varying amplitude in the inferior colliculus.

    Science.gov (United States)

    Zuk, Nathaniel; Delgutte, Bertrand

    2017-07-01

    Binaural cues occurring in natural environments are frequently time varying, either from the motion of a sound source or through interactions between the cues produced by multiple sources. Yet, a broad understanding of how the auditory system processes dynamic binaural cues is still lacking. In the current study, we directly compared neural responses in the inferior colliculus (IC) of unanesthetized rabbits to broadband noise with time-varying interaural time differences (ITD) with responses to noise with sinusoidal amplitude modulation (SAM) over a wide range of modulation frequencies. On the basis of prior research, we hypothesized that the IC, one of the first stages to exhibit tuning of firing rate to modulation frequency, might use a common mechanism to encode time-varying information in general. Instead, we found weaker temporal coding for dynamic ITD compared with amplitude modulation and stronger effects of adaptation for amplitude modulation. The differences in temporal coding of dynamic ITD compared with SAM at the single-neuron level could be a neural correlate of "binaural sluggishness," the inability to perceive fluctuations in time-varying binaural cues at high modulation frequencies, for which a physiological explanation has so far remained elusive. At ITD-variation frequencies of 64 Hz and above, where a temporal code was less effective, noise with a dynamic ITD could still be distinguished from noise with a constant ITD through differences in average firing rate in many neurons, suggesting a frequency-dependent tradeoff between rate and temporal coding of time-varying binaural information.NEW & NOTEWORTHY Humans use time-varying binaural cues to parse auditory scenes comprising multiple sound sources and reverberation. However, the neural mechanisms for doing so are poorly understood. Our results demonstrate a potential neural correlate for the reduced detectability of fluctuations in time-varying binaural information at high speeds, as occurs in

  5. Application of a Statistical Linear Time-Varying System Model of High Grazing Angle Sea Clutter for Computing Interference Power

    Science.gov (United States)

    2017-12-08

    formulae for the clutter autocorrelation with the hope that these mathematical tools can be useful in the design of clutter mitigation signal...varying (LTV) system theory, particularly in the case of wide-sense stationary uncorrelated scattering (WSSUS) was first put on firm mathematical ...is only valid over a single coherent processing interval (CPI) • Over a single CPI, the range to target(s) is roughly constant • The lag variable τ

  6. Plant cytokinin signalling.

    Science.gov (United States)

    Keshishian, Erika A; Rashotte, Aaron M

    2015-01-01

    Cytokinin is an essential plant hormone that is involved in a wide range of plant growth and developmental processes which are controlled through its signalling pathway. Cytokinins are a class of molecules that are N(6)-substituted adenine derivatives, such as isopentenyl adenine, and trans- and cis-zeatin, which are common in most plants. The ability to perceive and respond to cytokinin occurs through a modified bacterial two-component pathway that functions via a multi-step phosphorelay. This cytokinin signalling process is a crucial part of almost all stages of plant life, from embryo patterning to apical meristem regulation, organ development and eventually senescence. The cytokinin signalling pathway involves the co-ordination of three types of proteins: histidine kinase receptors to perceive the signal, histidine phosphotransfer proteins to relay the signal, and response regulators to provide signal output. This pathway contains both positive and negative elements that function in a complex co-ordinated manner to control cytokinin-regulated plant responses. Although much is known about how this cytokinin signal is perceived and initially regulated, there are still many avenues that need to be explored before the role of cytokinin in the control of plant processes is fully understood. © 2015 Authors; published by Portland Press Limited.

  7. Varying stratospheric responses to tropical Atlantic SST forcing from early to late winter

    Science.gov (United States)

    Rao, Jian; Ren, Rongcai

    2017-11-01

    Using multiple reanalysis datasets and model simulations, we begin in this study by isolating the tropical Atlantic Ocean (TAO) sea surface temperature (SST) signals that are independent from ENSO, and then investigate their influences on the northern winter stratosphere. It is revealed that TAO SST forcing does indeed have significant effects on the northern winter stratosphere, but these effects vary from early to late winter in a way that explains the overall insignificant effect when the seasonal average is considered. The stratospheric polar vortex is anomalously weaker/warmer in November-December, stronger/colder in January-March, and weaker/warmer again in April-May during warm TAO years. The varying impacts of the TAO forcing on the extratropical stratosphere are related to a three-stage response of the extratropical troposphere to the TAO forcing during cold season. The tropospheric circulation exhibits a negative North Atlantic Oscillation-like response during early winter, an eastward propagating Rossby wave pattern in mid-to-late winter, and a meridional dipole over North America in spring. Associated with this is varying planetary wave activity in the stratosphere, manifested as an increase in early winter, a decrease in mid-to-late winter, and an increase again in spring. The varying modulation of stratospheric circulation by TAO forcing is consistently confirmed in three reanalysis datasets, and model simulations (fully coupled model and its component AGCM). The exception to the robustness of this verification is that the circumpolar wind response in the fully coupled model is relatively weaker, and that in its component AGCM appears a month later than observed.

  8. Changes in the regulation of the Notch signaling pathway are temporally correlated with regenerative failure in the mouse cochlea

    Directory of Open Access Journals (Sweden)

    Juan Cristobal Maass

    2015-03-01

    Full Text Available Sensorineural hearing loss is most commonly caused by the death of hair cells in the organ of Corti, and once lost, mammalian hair cells do not regenerate. In contrast, other vertebrates such as birds can regenerate hair cells by stimulating division and differentiation of neighboring supporting cells. We currently know little of the genetic networks which become active in supporting cells when hair cells die and that are activated in experimental models of hair cell regeneration.. Several studies have shown that neonatal mammalian cochlear supporting cells are able to trans-differentiate into hair cells when cultured in conditions in which the Notch signaling pathway is blocked. We now show that the ability of cochlear supporting cells to trans-differentiate declines precipitously after birth, such that supporting cells from six-day-old mouse cochlea are entirely unresponsive to a blockade of the Notch pathway. We show that this trend is seen regardless of whether the Notch pathway is blocked with gamma secretase inhibitors, or by antibodies against the Notch1 receptor, suggesting that the action of gamma secretase inhibitors on neonatal supporting cells is likely to be by inhibiting Notch receptor cleavage. The loss of responsiveness to inhibition of the Notch pathway in the first postnatal week is due in part to a down-regulation of Notch receptors and ligands, and we show that this down-regulation persists in the adult animal, even under conditions of noise damage. Our data suggest that the Notch pathway is used to establish the repeating pattern of hair cells and supporting cells in the organ of Corti, but is not required to maintain this cellular mosaic once the production of hair cells and supporting cells is completed. Our results have implications for the proposed used of Notch pathway inhibitors in hearing restoration therapies.

  9. Tacholess Envelope Order Analysis and Its Application to Fault Detection of Rolling Element Bearings with Varying Speeds

    Science.gov (United States)

    Zhao, Ming; Lin, Jing; Xu, Xiaoqiang; Lei, Yaguo

    2013-01-01

    Vibration analysis is an effective tool for the condition monitoring and fault diagnosis of rolling element bearings. Conventional diagnostic methods are based on the stationary assumption, thus they are not applicable to the diagnosis of bearings working under varying speed. This constraint limits the bearing diagnosis to the industrial application significantly. In order to extend the conventional diagnostic methods to speed variation cases, a tacholess envelope order analysis technique is proposed in this paper. In the proposed technique, a tacholess order tracking (TLOT) method is first introduced to extract the tachometer information from the vibration signal itself. On this basis, an envelope order spectrum (EOS) is utilized to recover the bearing characteristic frequencies in the order domain. By combining the advantages of TLOT and EOS, the proposed technique is capable of detecting bearing faults under varying speeds, even without the use of a tachometer. The effectiveness of the proposed method is demonstrated by both simulated signals and real vibration signals collected from locomotive roller bearings with faults on inner race, outer race and rollers, respectively. Analyzed results show that the proposed method could identify different bearing faults effectively and accurately under speed varying conditions. PMID:23959244

  10. Tacholess Envelope Order Analysis and Its Application to Fault Detection of Rolling Element Bearings with Varying Speeds

    Directory of Open Access Journals (Sweden)

    Ming Zhao

    2013-08-01

    Full Text Available Vibration analysis is an effective tool for the condition monitoring and fault diagnosis of rolling element bearings. Conventional diagnostic methods are based on the stationary assumption, thus they are not applicable to the diagnosis of bearings working under varying speed. This constraint limits the bearing diagnosis to the industrial application significantly. In order to extend the conventional diagnostic methods to speed variation cases, a tacholess envelope order analysis technique is proposed in this paper. In the proposed technique, a tacholess order tracking (TLOT method is first introduced to extract the tachometer information from the vibration signal itself. On this basis, an envelope order spectrum (EOS is utilized to recover the bearing characteristic frequencies in the order domain. By combining the advantages of TLOT and EOS, the proposed technique is capable of detecting bearing faults under varying speeds, even without the use of a tachometer. The effectiveness of the proposed method is demonstrated by both simulated signals and real vibration signals collected from locomotive roller bearings with faults on inner race, outer race and rollers, respectively. Analyzed results show that the proposed method could identify different bearing faults effectively and accurately under speed varying conditions.

  11. Signal flow analysis

    CERN Document Server

    Abrahams, J R; Hiller, N

    1965-01-01

    Signal Flow Analysis provides information pertinent to the fundamental aspects of signal flow analysis. This book discusses the basic theory of signal flow graphs and shows their relation to the usual algebraic equations.Organized into seven chapters, this book begins with an overview of properties of a flow graph. This text then demonstrates how flow graphs can be applied to a wide range of electrical circuits that do not involve amplification. Other chapters deal with the parameters as well as circuit applications of transistors. This book discusses as well the variety of circuits using ther

  12. Scaling of muon remote sensing signals

    Energy Technology Data Exchange (ETDEWEB)

    Canavan, Gregory H [Los Alamos National Laboratory

    2009-01-01

    Few hundred MeV muon beams can penetrate vessels, detect nuclear materials, and differentiate between them from distances of several hundred meters. A companion report provides point estimates of the beam and detector parameters required to do so. This note varies the most sensitive parameters to examine performance over a range of scenarios. In the process it examines the results of the IDA analysis of muon interrogation, finding no serious discrepancies in the cases and parameters it examined, although some parameters are admittedly somewhat arbitrary. This note concentrates on the sensitivity of performance to beam size and to signature path length in targets, i.e., the sizes of the targets and vessels. The main results are shown in the figures. The companion report provides a useful framework for analysis, although it concentrates on a few, perhaps atypical examples. This note uses that framework to explore the beam and standoff requirements for a wider range of engagements. It primarily studies the impact of beam radius and area at varying and constant and fixed dose, and varying vessel thickness. The first two figures show quite distinct variations of signal gammas, background levels, and signal to noise ratios, but their main result is that the signal to noise ratios greater than unity essential for practical application can be achieved at beam radii up to about 1 m. Imposition of required dose limits in Fig. 2 has little impact on that result. The third figure indicates that adequate signal to noise ratios are achievable for thicknesses up to 4-5 m. Those ranges could be improved by smaller beams and other improvements, but exploring them in detail should probably await the improvement of the elements of the model that are stressed for thicker vessels.

  13. Design of crusher liner based on time - varying uncertainty theory

    Science.gov (United States)

    Tang, J. C.; Shi, B. Q.; Yu, H. J.; Wang, R. J.; Zhang, W. Y.

    2017-09-01

    This article puts forward the time-dependent design method considering the load fluctuation factors for the liner based on the time-varying uncertainty theory. In this method, the time-varying uncertainty design model of liner is constructed by introducing the parameters that affect the wear rate, the volatility and the drift rate. Based on the design example, the timevarying design outline of the moving cone liner is obtained. Based on the theory of minimum wear, the gap curve of wear resistant cavity is designed, and the optimized cavity is obtained by the combination of the thickness of the cone and the cavity gap. Taking the PYGB1821 multi cylinder hydraulic cone crusher as an example, it is proved that the service life of the new liner is improved by more than 14.3%.

  14. Poverty Index With Time Varying Consumption and Income Distributions

    CERN Document Server

    Chattopadhyay, Amit K; Mallick, Sushanta K

    2016-01-01

    In a recent work (Chattopadhyay, A. K. et al, Europhys. Lett. {\\bf 91}, 58003, 2010) based on food consumption statistics, we showed how a stochastic agent based model could represent the time variation of the income distribution statistics in a developing economy, thereby defining an alternative \\enquote{poverty index} (PI) that largely agreed with poverty gap index data. This PI used two variables, the probability density function of the income statistics and a consumption deprivation (CD) function, representing the shortfall in the minimum consumption needed for survival. Since the time dependence of the CD function was introduced there through data extrapolation only and not through an endogenous time dependent series, this model left unexplained how the minimum consumption needed for survival varies with time. The present article overcomes these limitations and arrives at a new unified theoretical structure through time varying consumption and income distributions where trade is only allowed when the inc...

  15. Local Feature Learning for Face Recognition under Varying Poses

    DEFF Research Database (Denmark)

    Duan, Xiaodong; Tan, Zheng-Hua

    2015-01-01

    In this paper, we present a local feature learning method for face recognition to deal with varying poses. As opposed to the commonly used approaches of recovering frontal face images from profile views, the proposed method extracts the subject related part from a local feature by removing the pose...... related part in it on the basis of a pose feature. The method has a closed-form solution, hence being time efficient. For performance evaluation, cross pose face recognition experiments are conducted on two public face recognition databases FERET and FEI. The proposed method shows a significant...... recognition improvement under varying poses over general local feature approaches and outperforms or is comparable with related state-of-the-art pose invariant face recognition approaches. Copyright ©2015 by IEEE....

  16. Performance of Traffic Noise Barriers with Varying Cross-Section

    Directory of Open Access Journals (Sweden)

    Sanja Grubeša

    2011-05-01

    Full Text Available The efficiency of noise barriers largely depends on their geometry. In this paper, the performance of noise barriers was simulated using the numerical Boundary Element Method (BEM. Traffic noise was particularly considered with its standardized noise spectrum adapted to human hearing. The cross-section of the barriers was varied with the goal of finding the optimum shape in comparison to classical rectangular barriers. The barrier performance was calculated at different receiver points for a fixed barrier height and source position. The magnitude of the insertion loss parameter was used to evaluate the performance change, both in one-third octave bands and as the broadband mean insertion loss value. The proposed barriers of varying cross-section were also compared with a typical T-shape barrier of the same height.

  17. Fault detection in reciprocating compressor valves under varying load conditions

    Science.gov (United States)

    Pichler, Kurt; Lughofer, Edwin; Pichler, Markus; Buchegger, Thomas; Klement, Erich Peter; Huschenbett, Matthias

    2016-03-01

    This paper presents a novel approach for detecting cracked or broken reciprocating compressor valves under varying load conditions. The main idea is that the time frequency representation of vibration measurement data will show typical patterns depending on the fault state. The problem is to detect these patterns reliably. For the detection task, we make a detour via the two dimensional autocorrelation. The autocorrelation emphasizes the patterns and reduces noise effects. This makes it easier to define appropriate features. After feature extraction, classification is done using logistic regression and support vector machines. The method's performance is validated by analyzing real world measurement data. The results will show a very high detection accuracy while keeping the false alarm rates at a very low level for different compressor loads, thus achieving a load-independent method. The proposed approach is, to our best knowledge, the first automated method for reciprocating compressor valve fault detection that can handle varying load conditions.

  18. Modelling Time-Varying Volatility in Financial Returns

    DEFF Research Database (Denmark)

    Amado, Cristina; Laakkonen, Helinä

    2014-01-01

    The “unusually uncertain” phase in the global financial markets has inspired many researchers to study the effects of ambiguity (or “Knightian uncertainty”) on the decisions made by investors and their implications for the capital markets. We contribute to this literature by using a modified...... being captured by a stable GARCH(1,1) process and the second driven by the level of uncertainty in the financial market....... version of the time-varying GARCH model of Amado and Teräsvirta (2013) to analyze whether the increasing uncertainty has caused excess volatility in the US and European government bond markets. In our model, volatility is multiplicatively decomposed into two time-varying conditional components: the first...

  19. Non-minimally coupled varying constants quantum cosmologies

    CERN Document Server

    Balcerzak, Adam

    2015-01-01

    We consider gravity theory with varying speed of light and varying gravitational constant. Both constants are represented by non-minimally coupled scalar fields. We examine the cosmological evolution in the near curvature singularity regime. We find that at the curvature singularity the speed of light goes to infinity while the gravitational constant vanishes. This corresponds to the Newton's Mechanics limit represented by one of the vertex of the Bronshtein-Zelmanov-Okun cube. The cosmological evolution includes both the pre-big-bang and post-big-bang phases separated by the curvature singularity. We also investigate the quantum counterpart of the considered theory and find the probability of transition of the universe from the collapsing pre-big-bang phase to the expanding post-big-bang phase.

  20. Non-minimally coupled varying constants quantum cosmologies

    Science.gov (United States)

    Balcerzak, Adam

    2015-04-01

    We consider gravity theory with varying speed of light and varying gravitational constant. Both constants are represented by non-minimally coupled scalar fields. We examine the cosmological evolution in the near curvature singularity regime. We find that at the curvature singularity the speed of light goes to infinity while the gravitational constant vanishes. This corresponds to the Newton's Mechanics limit represented by one of the vertex of the Bronshtein-Zelmanov-Okun cube [1,2]. The cosmological evolution includes both the pre-big-bang and post-big-bang phases separated by the curvature singularity. We also investigate the quantum counterpart of the considered theory and find the probability of transition of the universe from the collapsing pre-big-bang phase to the expanding post-big-bang phase.

  1. Control of Linear Parameter Varying Systems with Applications

    CERN Document Server

    Mohammadpour, Javad

    2012-01-01

    Control of Linear Parameter Varying Systems with Applications compiles state-of-the-art contributions on novel analytical and computational methods to address system modeling and identification, complexity reduction, performance analysis and control design for time-varying and nonlinear systems in the LPV framework. The book has an interdisciplinary character by emphasizing techniques that can be commonly applied in various engineering fields. It also includes a rich collection of illustrative applications in diverse domains to substantiate the effectiveness of the design methodologies and provide pointers to open research directions. The book is divided into three parts. The first part collects chapters of a more tutorial character on the background of LPV systems modeling and control. The second part gathers chapters devoted to the theoretical advancement of LPV analysis and synthesis methods to cope with the design constraints such as uncertainties and time delay. The third part of the volume showcases con...

  2. Hemolymph drop impact outcomes on surfaces with varying wettability

    Science.gov (United States)

    Milionis, Athanasios; Ghokulla Krishnan, K.; Loth, Eric

    2015-08-01

    Insect fouling from coagulated hemolymph and exoskeleton parts is a major challenge in the aerospace industry for the next generation of aerodynamic surfaces, which will employ laminar flow that requires extremely smooth surfaces. However, the wetting physics and dynamics of hemolymph (insect blood) on surfaces are not well understood. The present study seeks to gain a fundamental insight on the effect of surface wetting characteristics and dynamics resulting from a hemolymph drop impact, the first such study. In particular, hemolymph drops extracted from Acheta domesticus were dispensed from a range of heights to vary the kinetic impact on surfaces, which had widely varying water wetting behavior (from superhydrophilic to superhydrophobic). The impact dynamics were investigated with high-speed imaging while the dried residues were studied with optical microscopy. It was found that a superhydrophobic surface (based on thermoplastic with silica nano-particles) was able to significantly reduce hemolymph drop spreading, and even provide complete rebound when impacting on inclined surfaces.

  3. Signal Station Inspection Reports

    Data.gov (United States)

    National Oceanic and Atmospheric Administration, Department of Commerce — Handwritten reports resulting from detailed inspections of US Army Signal Service Stations, 1871-1889. Features reported included instrument exposure and condition,...

  4. Transmembrane Signalling: Membrane messengers

    Science.gov (United States)

    Cockroft, Scott L.

    2017-05-01

    Life has evolved elaborate means of communicating essential chemical information across cell membranes. Inspired by biology, two new artificial mechanisms have now been developed that use synthetic messenger molecules to relay chemical signals into or across lipid membranes.

  5. Foundations of signal processing

    CERN Document Server

    Vetterli, Martin; Goyal, Vivek K

    2014-01-01

    This comprehensive and engaging textbook introduces the basic principles and techniques of signal processing, from the fundamental ideas of signals and systems theory to real-world applications. Students are introduced to the powerful foundations of modern signal processing, including the basic geometry of Hilbert space, the mathematics of Fourier transforms, and essentials of sampling, interpolation, approximation and compression. The authors discuss real-world issues and hurdles to using these tools, and ways of adapting them to overcome problems of finiteness and localisation, the limitations of uncertainty and computational costs. Standard engineering notation is used throughout, making mathematical examples easy for students to follow, understand and apply. It includes over 150 homework problems and over 180 worked examples, specifically designed to test and expand students' understanding of the fundamentals of signal processing, and is accompanied by extensive online materials designed to aid learning, ...

  6. Acoustic MIMO signal processing

    CERN Document Server

    Huang, Yiteng; Chen, Jingdong

    2006-01-01

    A timely and important book addressing a variety of acoustic signal processing problems under multiple-input multiple-output (MIMO) scenarios. It uniquely investigates these problems within a unified framework offering a novel and penetrating analysis.

  7. Traffic Signal Cycle Lengths

    Data.gov (United States)

    Town of Chapel Hill, North Carolina — Traffic signal location list for the town of Chapel Hill. This data set includes light cycle information as well as as intersection information.The Town of Chapel...

  8. Ultrahigh bandwidth signal processing

    DEFF Research Database (Denmark)

    Oxenløwe, Leif Katsuo

    2016-01-01

    Optical time lenses have proven to be very versatile for advanced optical signal processing. Based on a controlled interplay between dispersion and phase-modulation by e.g. four-wave mixing, the processing is phase-preserving, an hence useful for all types of data signals including coherent multi......-level modulation founats. This has enabled processing of phase-modulated spectrally efficient data signals, such as orthogonal frequency division multiplexed (OFDM) signa In that case, a spectral telescope system was used, using two time lenses with different focal lengths (chirp rates), yielding a spectral...... regeneratio These operations require a broad bandwidth nonlinear platform, and novel photonic integrated nonlinear platform like aluminum gallium arsenide nano-waveguides used for 1.28 Tbaud optical signal processing will be described....

  9. Utilization of varying proportions of maize milling waste and cowpea ...

    African Journals Online (AJOL)

    Dry matter intake (DMI), daily weight gain (DWG), feed efficiency and economics of including varying levels of MMW and CPS were studied for eight weeks. The DMI and DWG were significantly (p<0.05) higher for diets C, D and E (59.40, 57.60 and 61.00 g/day and 11.94, 10.89 and 11.42 g/day respectively) compared to ...

  10. The value premium and time-varying volatility

    OpenAIRE

    Li, X.; Brooks, C.; Miffre, J.

    2009-01-01

    Numerous studies have documented the failure of the static and conditional capital asset pricing models to explain the difference in returns between value and growth stocks. This paper examines the post-1963 value premium by employing a model that captures the time-varying total risk of the value-minus-growth portfolios. Our results show that the time-series of value premia is strongly and positively correlated with its volatility. This conclusion is robust to the criterion used to sort stock...

  11. Tracking time-varying parameters with local regression

    DEFF Research Database (Denmark)

    Joensen, Alfred Karsten; Nielsen, Henrik Aalborg; Nielsen, Torben Skov

    2000-01-01

    This paper shows that the recursive least-squares (RLS) algorithm with forgetting factor is a special case of a varying-coe\\$cient model, and a model which can easily be estimated via simple local regression. This observation allows us to formulate a new method which retains the RLS algorithm, bu......, but extends the algorithm by including polynomial approximations. Simulation results are provided, which indicates that this new method is superior to the classical RLS method, if the parameter variations are smooth....

  12. The Value Premium and Time-Varying Unsystematic Risk

    OpenAIRE

    Chris Brooks; Xiafei Li; Joelle Miffre

    2007-01-01

    Recent research has discussed the possible role of unsystematic risk in explaining equity returns. Simultaneously, but somehow independently, numerous other studies have documented the failure of the static and conditional capital asset pricing models to explain the differences in returns between value and growth stocks. This paper examines the post-1963 value premium by employing a model that captures the time-varying total risk of the value-minus-growth portfolios. In accordance with existi...

  13. Nutrient intake, digestibility and growth rate of rabbits fed varying ...

    African Journals Online (AJOL)

    Forty young rabbits were fed on five diets varying in cassava leaf meal (CLM} levels from 0% to 60%. Dry matter and nutrient intake and digestibility, weight gain and economics of CLM inclusion were determined The DMI (g/d) ranged from 44.24 (60% CLM) to 66.85 (15% CLM); daily live weight gain (LWG, g/d) from 8.43 ...

  14. Premorbid IQ varies across different definitions of schizophrenia

    DEFF Research Database (Denmark)

    Urfer Parnas, Annick; Jansson, Lennart; Handest, Peter

    2007-01-01

    The nature of the association between IQ and schizophrenia is still unclear. So far no study addressed this issue in relation to the breadth or scope of the very concept of schizophrenia. We examined the premorbid IQ in a polydiagnostic study with four classifications of schizophrenia: ICD-8/9, I...... of schizophrenia in relation to IQ revealed associations between low premorbid IQ and hallucinations as well as negative symptoms. It is concluded that premorbid IQ varies across different definitions of schizophrenia....

  15. Modest Advertising Signals Strength.

    OpenAIRE

    Ram Orzach; Per Baltzer Overgaard; Yair Tauman

    2001-01-01

    This paper presents a signaling model where both price and advertising expenditures are used as signals of the initially unobservable quality of a newly introduced experience good. Consumers can be either "fastidious" or "indifferent". Fastidious individuals place a greater value on a high-quality product and a lesser value on the low-quality product than do indifferent individuals. It is shown that a sensible separating equilibrium exists where both firms set their full information prices. H...

  16. Lipid Signaling in Tumorigenesis

    OpenAIRE

    Liu, Renyan; Huang, Ying

    2014-01-01

    Lipids are important cellular building blocks and components of signaling cascades. Deregulation of lipid metabolism or signaling is frequently linked to a variety of human diseases such as diabetes, cardiovascular diseases, and cancer. It is widely believed that lipid molecules or their metabolic products are involved in tumorigenic inflammation and thus, lipids are implicated as significant contributors or even primary triggers of tumorigenesis. Lipids are believed to directly or indirectly...

  17. Optical Signal Processing.

    Science.gov (United States)

    1983-11-30

    that the readaptation phenomena is minimized as signal components leave the tap weight plane (the accumulator). In principle, the performance could be...accumulators so that the readaptation phenomena caused by large values pleaving the accumulator are minimized. Several examples of the performance...the jammer signal. The system then goes into a " readaptation " phase where the new contributions to the tap weights must offset the older cont

  18. Twist defect in chiral photonic structures with spatially varying pitch

    Science.gov (United States)

    Chen, Jiun-Yeu; Chen, Lien-Wen

    2005-04-01

    The properties of photonic defect modes in a chiral photonic structure were investigated using the finite element method. By stacking two cholesteric liquid crystal (ChLC) films, the defect mode due to the introduction of a twist defect was considered in both cases of chiral structures with constant pitch and spatially varying pitch. Two types of linear pitch gradients for achieving a broadband reflection were analysed, and the number of chiral pitches required for establishing the stop band was simulated. The effect of a finite sample thickness on the energy density distribution of the defect mode and on the required polarization of the incident light to excite the defect mode was studied. In both cases of constant pitch and spatially varying pitch, an unusual crossover behaviour in reflection at the defect resonance wavelength of a single circularly polarized mode appears when the structure thickness increases beyond a specific value. The energy distribution inside the sample also reveals the unusual distribution. Two different resonance wavelengths can be created by a twist defect in the ChLC composite film with linearly varying pitch, while only one resonance wavelength can be created in the identical film with constant pitch.

  19. Modeling information diffusion in time-varying community networks

    Science.gov (United States)

    Cui, Xuelian; Zhao, Narisa

    2017-12-01

    Social networks are rarely static, and they typically have time-varying network topologies. A great number of studies have modeled temporal networks and explored social contagion processes within these models; however, few of these studies have considered community structure variations. In this paper, we present a study of how the time-varying property of a modular structure influences the information dissemination. First, we propose a continuous-time Markov model of information diffusion where two parameters, mobility rate and community attractiveness, are introduced to address the time-varying nature of the community structure. The basic reproduction number is derived, and the accuracy of this model is evaluated by comparing the simulation and theoretical results. Furthermore, numerical results illustrate that generally both the mobility rate and community attractiveness significantly promote the information diffusion process, especially in the initial outbreak stage. Moreover, the strength of this promotion effect is much stronger when the modularity is higher. Counterintuitively, it is found that when all communities have the same attractiveness, social mobility no longer accelerates the diffusion process. In addition, we show that the local spreading in the advantage group has been greatly enhanced due to the agglomeration effect caused by the social mobility and community attractiveness difference, which thus increases the global spreading.

  20. Delivery of continuously-varying stimuli using channelrhodopsin-2.

    Science.gov (United States)

    Tchumatchenko, Tatjana; Newman, Jonathan P; Fong, Ming-fai; Potter, Steve M

    2013-01-01

    To study sensory processing, stimuli are delivered to the sensory organs of animals and evoked neural activity is recorded downstream. However, noise and uncontrolled modulatory input can interfere with repeatable delivery of sensory stimuli to higher brain regions. Here we show how channelrhodopsin-2 (ChR2) can be used to deliver continuous, subthreshold, time-varying currents to neurons at any point along the sensory-motor pathway. To do this, we first deduce the frequency response function of ChR2 using a Markov model of channel kinetics. We then confirm ChR2's frequency response characteristics using continuously-varying optical stimulation of neurons that express one of three ChR2 variants. We find that wild-type ChR2 and the E123T/H134R mutant ("CheTA") can pass continuously-varying subthreshold stimuli with frequencies up to ~70 Hz. Additionally, we find that wild-type ChR2 exhibits a strong resonance at ~6-10 Hz. Together, these results indicate that ChR2-derived optogenetic tools are useful for delivering highly repeatable artificial stimuli that mimic in vivo synaptic bombardment.

  1. Online dynamic mode decomposition for time-varying systems

    Science.gov (United States)

    Zhang, Hao; Rowley, Clarence; Deem, Eric; Cattafesta, Louis

    2017-11-01

    Dynamic mode decomposition (DMD) is a popular technique for modal decomposition, flow analysis, and reduced-order modeling. In situations where a system is time varying, one would like to update the system's description online as time evolves. This work provides an efficient method for computing the DMD matrix in real time, updating the approximation of a system's dynamics as new data becomes available. The algorithm does not require storage of past data, and computes the exact DMD matrix using rank-1 updates. A weighting factor that places less weight on older data can be incorporated in a straightforward manner, making the method particularly well suited to time-varying systems. The efficiency of the method is compared against several existing DMD algorithms: for problems in which the state dimension is less than about 200, the proposed algorithm is the most efficient for real-time computation, and it can be orders of magnitude more efficient than the standard DMD algorithm. The method is demonstrated on several examples, including a time-varying linear system and a more complex example using data from a wind tunnel experiment. Supported by AFOSR Grant FA9550-14-1-0289, and by DARPA award HR0011-16-C-0116.

  2. Mass-varying massive gravity with k-essence

    Energy Technology Data Exchange (ETDEWEB)

    Tannukij, Lunchakorn [Mahidol University, Department of Physics, Faculty of Science, Bangkok (Thailand); Wongjun, Pitayuth [Naresuan University, The Institute for Fundamental Study, Phitsanulok (Thailand); Thailand Center of Excellence in Physics, Ministry of Education, Bangkok (Thailand)

    2016-01-15

    For a large class of mass-varying massive-gravity models, the graviton mass cannot provide the late-time cosmic expansion of the universe due to its vanishing at late time. In this work, we propose a new class of mass-varying massive gravity models, in which the graviton mass varies according to a kinetic term of a k-essence field. By using a more general form of the fiducial metric, we found a solution such that a non-vanishing graviton mass can drive the accelerated expansion of the universe at late time. We also perform dynamical analyses of such a model and find that without introducing the k-essence Lagrangian, the graviton mass can be responsible for both dark contents of the universe, namely dark energy, which drives the accelerated expansion of the universe, and non-relativistic matter, which plays the role of dark matter. Moreover, by including the k-essence Lagrangian, we find that it is possible to alleviate the so-called cosmic coincidence problem. (orig.)

  3. VariVis: a visualisation toolkit for variation databases

    Directory of Open Access Journals (Sweden)

    Smith Timothy D

    2008-04-01

    Full Text Available Abstract Background With the completion of the Human Genome Project and recent advancements in mutation detection technologies, the volume of data available on genetic variations has risen considerably. These data are stored in online variation databases and provide important clues to the cause of diseases and potential side effects or resistance to drugs. However, the data presentation techniques employed by most of these databases make them difficult to use and understand. Results Here we present a visualisation toolkit that can be employed by online variation databases to generate graphical models of gene sequence with corresponding variations and their consequences. The VariVis software package can run on any web server capable of executing Perl CGI scripts and can interface with numerous Database Management Systems and "flat-file" data files. VariVis produces two easily understandable graphical depictions of any gene sequence and matches these with variant data. While developed with the goal of improving the utility of human variation databases, the VariVis package can be used in any variation database to enhance utilisation of, and access to, critical information.

  4. Social contagions on time-varying community networks

    Science.gov (United States)

    Liu, Mian-Xin; Wang, Wei; Liu, Ying; Tang, Ming; Cai, Shi-Min; Zhang, Hai-Feng

    2017-05-01

    Time-varying community structures exist widely in real-world networks. However, previous studies on the dynamics of spreading seldom took this characteristic into account, especially those on social contagions. To study the effects of time-varying community structures on social contagions, we propose a non-Markovian social contagion model on time-varying community networks based on the activity-driven network model. A mean-field theory is developed to analyze the proposed model. Through theoretical analyses and numerical simulations, two hierarchical features of the behavior adoption processes are found. That is, when community strength is relatively large, the behavior can easily spread in one of the communities, while in the other community the spreading only occurs at higher behavioral information transmission rates. Meanwhile, in spatial-temporal evolution processes, hierarchical orders are observed for the behavior adoption. Moreover, under different information transmission rates, three distinctive patterns are demonstrated in the change of the whole network's final adoption proportion along with the growing community strength. Within a suitable range of transmission rate, an optimal community strength can be found that can maximize the final adoption proportion. Finally, compared with the average activity potential, the promoting or inhibiting of social contagions is much more influenced by the number of edges generated by active nodes.

  5. On enhanced time-varying distributed H systems

    Directory of Open Access Journals (Sweden)

    Sergey Verlan

    2002-11-01

    Full Text Available An enhanced time-varying distributed H system (ETVDH system is a slightly different definition of the time-varying distributed H system (TVDH system [9] and it was proposed by M. Margenstern and Yu. Rogozhin in [4] under the name of "extended time-varying distributed H system''. The main difference is that the components of the ETVDH system are H systems and therefore splicing rules may be applied more than once as it is done in TVDH systems. This leads to difficulties in investigating the behavior of such systems because they have a higher level of parallelism. It is proved that ETVDH systems of degree 2 (i.e. with 2 components generate all recursively enumerable languages in a sequential way [7] and that ETVDH systems of degree 4 generate all recursively enumerable languages in a "parallel'' way, modelling a formal type-0 grammar [11]. In this paper we improve the last result and we present an ETVDH system of degree 3 which generates all recursively enumerable languages modelling type-0 formal grammars. The problem of the existence of ETVDH systems of degree 2 which generate all recursively enumerable languages in a "parallel'' way is left open.

  6. Radar antenna pointing for optimized signal to noise ratio.

    Energy Technology Data Exchange (ETDEWEB)

    Doerry, Armin Walter; Marquette, Brandeis

    2013-01-01

    The Signal-to-Noise Ratio (SNR) of a radar echo signal will vary across a range swath, due to spherical wavefront spreading, atmospheric attenuation, and antenna beam illumination. The antenna beam illumination will depend on antenna pointing. Calculations of geometry are complicated by the curved earth, and atmospheric refraction. This report investigates optimizing antenna pointing to maximize the minimum SNR across the range swath.

  7. Varying hemin concentrations affect Porphyromonas gingivalis strains differently.

    Science.gov (United States)

    Ohya, Manabu; Cueno, Marni E; Tamura, Muneaki; Ochiai, Kuniyasu

    2016-05-01

    Porphyromonas gingivalis requires heme to grow, however, heme availability and concentration in the periodontal pockets vary. Fluctuations in heme concentration may affect each P. gingivalis strain differently, however, this was never fully demonstrated. Here, we elucidated the effects of varying hemin concentrations in representative P. gingivalis strains. Throughout this study, representative P. gingivalis strains [FDC381 (type I), MPWIb-01 (type Ib), TDC60 (type II), ATCC49417 (type III), W83 (type IV), and HNA99 (type V)] were used and grown for 24 h in growth media under varying hemin concentrations (5 × , 1 × , 0.5 × , 0.1 × ). Samples were lysed and protein standardized. Arg-gingipain (Rgp), H2O2, and superoxide dismutase (SOD) levels were subsequently measured. We focused our study on 24 h-grown strains which excluded MPWIb-01 and HNA99. Rgp activity among the 4 remaining strains varied with Rgp peaking at: 1 × for FDC381, 5 × for TDC60, 0.5 × for ATCC49417, 5 × and 0.5 × for W83. With regards to H2O2 and SOD amounts: FDC381 had similar H2O2 amounts in all hemin concentrations while SOD levels varied; TDC60 had the lowest H2O2 amount at 1 × while SOD levels became higher in relation to hemin concentration; ATCC49417 also had similar H2O2 amounts in all hemin concentrations while SOD levels were higher at 1 × and 0.5 × ; and W83 had statistically similar H2O2 and SOD amounts regardless of hemin concentration. Our results show that variations in hemin concentration affect each P. gingivalis strain differently. Published by Elsevier Ltd.

  8. Digital Signal Processing applied to Physical Signals

    CERN Document Server

    Alberto, Diego; Musa, L

    2011-01-01

    It is well known that many of the scientific and technological discoveries of the XXI century will depend on the capability of processing and understanding a huge quantity of data. With the advent of the digital era, a fully digital and automated treatment can be designed and performed. From data mining to data compression, from signal elaboration to noise reduction, a processing is essential to manage and enhance features of interest after every data acquisition (DAQ) session. In the near future, science will go towards interdisciplinary research. In this work there will be given an example of the application of signal processing to different fields of Physics from nuclear particle detectors to biomedical examinations. In Chapter 1 a brief description of the collaborations that allowed this thesis is given, together with a list of the publications co-produced by the author in these three years. The most important notations, definitions and acronyms used in the work are also provided. In Chapter 2, the last r...

  9. Time-varying value of electric energy efficiency

    Energy Technology Data Exchange (ETDEWEB)

    Mims, Natalie A.; Eckman, Tom; Goldman, Charles

    2017-06-30

    Electric energy efficiency resources save energy and may reduce peak demand. Historically, quantification of energy efficiency benefits has largely focused on the economic value of energy savings during the first year and lifetime of the installed measures. Due in part to the lack of publicly available research on end-use load shapes (i.e., the hourly or seasonal timing of electricity savings) and energy savings shapes, consideration of the impact of energy efficiency on peak demand reduction (i.e., capacity savings) has been more limited. End-use load research and the hourly valuation of efficiency savings are used for a variety of electricity planning functions, including load forecasting, demand-side management and evaluation, capacity and demand response planning, long-term resource planning, renewable energy integration, assessing potential grid modernization investments, establishing rates and pricing, and customer service. This study reviews existing literature on the time-varying value of energy efficiency savings, provides examples in four geographically diverse locations of how consideration of the time-varying value of efficiency savings impacts the calculation of power system benefits, and identifies future research needs to enhance the consideration of the time-varying value of energy efficiency in cost-effectiveness screening analysis. Findings from this study include: -The time-varying value of individual energy efficiency measures varies across the locations studied because of the physical and operational characteristics of the individual utility system (e.g., summer or winter peaking, load factor, reserve margin) as well as the time periods during which savings from measures occur. -Across the four locations studied, some of the largest capacity benefits from energy efficiency are derived from the deferral of transmission and distribution system infrastructure upgrades. However, the deferred cost of such upgrades also exhibited the greatest range

  10. Complex courtship displays facilitate male reproductive success and plasticity in signaling across variable environments

    Directory of Open Access Journals (Sweden)

    Dustin J. WILGERS, Eileen A. HEBETS

    2011-04-01

    Full Text Available Effective signal transmission is essential for communication. In environments where signal transmission is highly variable, signalers may utilize complex signals, which incorporate multiple components and modalities, to maintain effective communication. Male Rabidosa rabida wolf spiders produce complex courtship signals, consisting of both visual and seismic components. We test the hypothesis that the complex signaling of R. rabida contributes to male reproductive success in variable signaling environments. We first examine the condition-dependence of ornamentation (a presumed visual signal and seismic signal components and find that both may provide potentially redundant information on foraging history. Next, we assessed reproductive success across manipulated signaling environments that varied in the effectiveness of visual and/or seismic signal transmission. In environments where only one signal could be successfully transmitted (e.g., visual or seismic, pairs were still able to successfully copulate. Additionally, we found that males altered their courtship display depending on the current signaling environment. Specifically, males reduced their use of a visual display component in signaling environments where visual signal transmission was ablated. Incorporating signals in multiple modalities not only enables R. rabida males to maintain copulation success across variable signaling environments, but it also enables males to adjust their composite courtship display to current signaling conditions [Current Zoology 57 (2: 175–186, 2011].

  11. Mitigation of time-varying distortions in Nyquist-WDM systems using machine learning

    Science.gov (United States)

    Granada Torres, Jhon J.; Varughese, Siddharth; Thomas, Varghese A.; Chiuchiarelli, Andrea; Ralph, Stephen E.; Cárdenas Soto, Ana M.; Guerrero González, Neil

    2017-11-01

    We propose a machine learning-based nonsymmetrical demodulation technique relying on clustering to mitigate time-varying distortions derived from several impairments such as IQ imbalance, bias drift, phase noise and interchannel interference. Experimental results show that those impairments cause centroid movements in the received constellations seen in time-windows of 10k symbols in controlled scenarios. In our demodulation technique, the k-means algorithm iteratively identifies the cluster centroids in the constellation of the received symbols in short time windows by means of the optimization of decision thresholds for a minimum BER. We experimentally verified the effectiveness of this computationally efficient technique in multicarrier 16QAM Nyquist-WDM systems over 270 km links. Our nonsymmetrical demodulation technique outperforms the conventional QAM demodulation technique, reducing the OSNR requirement up to ∼0.8 dB at a BER of 1 × 10-2 for signals affected by interchannel interference.

  12. Guidance, Navigation and Control of Unmanned Airships under Time-Varying Wind for Extended Surveillance

    Directory of Open Access Journals (Sweden)

    Ghassan Atmeh

    2016-02-01

    Full Text Available This paper deals with the control of lighter-than-air vehicles, more specifically the design of an integrated guidance, navigation and control (GNC scheme that is capable of navigating an airship through a series of constant-altitude, planar waypoints. Two guidance schemes are introduced, a track-specific guidance law and a proportional navigation guidance law, that provide the required signals to the corresponding controllers based on the airship position relative to a target waypoint. A novel implementation of the extended Kalman filter, namely the scheduled extended Kalman filter, estimates the required states and wind speed to enhance the performance of the track-specific guidance law in the presence of time-varying wind. The performance of the GNC system is tested using a high fidelity nonlinear dynamic simulation for a variety of flying conditions. Representative results illustrate the performance of the integrated system for chosen flight conditions.

  13. Threshold-Based Bit Error Rate for Stopping Iterative Turbo Decoding in a Varying SNR Environment

    Science.gov (United States)

    Mohamad, Roslina; Harun, Harlisya; Mokhtar, Makhfudzah; Adnan, Wan Azizun Wan; Dimyati, Kaharudin

    2017-01-01

    Online bit error rate (BER) estimation (OBE) has been used as a stopping iterative turbo decoding criterion. However, the stopping criteria only work at high signal-to-noise ratios (SNRs), and fail to have early termination at low SNRs, which contributes to an additional iteration number and an increase in computational complexity. The failure of the stopping criteria is caused by the unsuitable BER threshold, which is obtained by estimating the expected BER performance at high SNRs, and this threshold does not indicate the correct termination according to convergence and non-convergence outputs (CNCO). Hence, in this paper, the threshold computation based on the BER of CNCO is proposed for an OBE stopping criterion (OBEsc). From the results, OBEsc is capable of terminating early in a varying SNR environment. The optimum number of iterations achieved by the OBEsc allows huge savings in decoding iteration number and decreasing the delay of turbo iterative decoding.

  14. Comparison of different Kalman filter approaches in deriving time varying connectivity from EEG data.

    Science.gov (United States)

    Ghumare, Eshwar; Schrooten, Maarten; Vandenberghe, Rik; Dupont, Patrick

    2015-08-01

    Kalman filter approaches are widely applied to derive time varying effective connectivity from electroencephalographic (EEG) data. For multi-trial data, a classical Kalman filter (CKF) designed for the estimation of single trial data, can be implemented by trial-averaging the data or by averaging single trial estimates. A general linear Kalman filter (GLKF) provides an extension for multi-trial data. In this work, we studied the performance of the different Kalman filtering approaches for different values of signal-to-noise ratio (SNR), number of trials and number of EEG channels. We used a simulated model from which we calculated scalp recordings. From these recordings, we estimated cortical sources. Multivariate autoregressive model parameters and partial directed coherence was calculated for these estimated sources and compared with the ground-truth. The results showed an overall superior performance of GLKF except for low levels of SNR and number of trials.

  15. Statistical-Mechanical Analysis of LMS Algorithm for Time-Varying Unknown System

    Science.gov (United States)

    Ishibushi, Norihiro; Kajikawa, Yoshinobu; Miyoshi, Seiji

    2017-02-01

    We analyze the behaviors of the least-mean-square algorithm for a time-varying unknown system using a statistical-mechanical method. Cross-correlations between the elements of a primary path and those of an adaptive filter and autocorrelations of the elements of the adaptive filter are treated as macroscopic variables. We obtain simultaneous differential equations that describe the dynamical behaviors of the macroscopic variables under conditions in which the tapped delay line is sufficiently long. We analytically show the existence of an optimal step size. This result is supporting evidence of Widrow et al.'s pioneering work that clarified the trade-off between the noise misadjustment and the lag misadjustment. Furthermore, we obtain the exact solution of the optimal step size in the case of a white reference signal. The derived theory includes the behaviors for a time-constant unknown system as a special case.

  16. miR-122 regulates p53/Akt signalling and the chemotherapy-induced apoptosis in cutaneous T-cell lymphoma.

    Directory of Open Access Journals (Sweden)

    Valentina Manfè

    Full Text Available Advanced cutaneous T-cell lymphoma (CTCL is resistant to chemotherapy and presents a major area of medical need. In view of the known role of microRNAs (miRNAs in the regulation of cellular signalling, we aimed to identify the functionally important miRNA species, which regulate apoptosis in CTCL. Using a recently established model in which apoptosis of CTCL cell lines is induced by Notch-1 inhibition by γ-secretase inhibitors (GSIs, we found that miR-122 was significantly increased in the apoptotic cells. miR-122 up-regulation was not specific for GSI-1 but was also seen during apoptosis induced by chemotherapies including doxorubicin and proteasome blockers (bortezomib, MG132. miR-122 was not expressed in quiescent T-cells, but was detectable in CTCL: in lesional skin in mycosis fungoides and in Sézary cells purified from peripheral blood. In situ hybridization results showed that miR-122 was expressed in the malignant T-cell infiltrate and increased in the advanced stage mycosis fungoides. Surprisingly, miR-122 overexpression decreased the sensitivity to the chemotherapy-induced apoptosis via a signaling circuit involving the activation of Akt and inhibition of p53. We have also shown that induction of miR-122 occurred via p53 and that p53 post-transcriptionally up-regulated miR-122. miR-122 is thus an amplifier of the antiapoptotic Akt/p53 circuit and it is conceivable that a pharmacological intervention in this pathway may provide basis for novel therapies for CTCL.

  17. Development of an Improved Time Varying Loudness Model with the Inclusion of Binaural Loudness Summation

    Science.gov (United States)

    Charbonneau, Jeremy

    As the perceived quality of a product is becoming more important in the manufacturing industry, more emphasis is being placed on accurately predicting the sound quality of everyday objects. This study was undertaken to improve upon current prediction techniques with regard to the psychoacoustic descriptor of loudness and an improved binaural summation technique. The feasibility of this project was first investigated through a loudness matching experiment involving thirty-one subjects and pure tones of constant sound pressure level. A dependence of binaural summation on frequency was observed which had previously not been a subject of investigation in the reviewed literature. A follow-up investigation was carried out with forty-eight volunteers and pure tones of constant sensation level. Contrary to existing theories in literature the resulting loudness matches revealed an amplitude versus frequency relationship which confirmed the perceived increase in loudness when a signal was presented to both ears simultaneously as opposed to one ear alone. The resulting trend strongly indicated that the higher the frequency of the presented signal, the greater the increase in observed binaural summation. The results from each investigation were summarized into a single binaural summation algorithm and inserted into an improved time-varying loudness model. Using experimental techniques, it was demonstrated that the updated binaural summation algorithm was a considerable improvement over the state of the art approach for predicting the perceived binaural loudness. The improved function retained the ease of use from the original model while additionally providing accurate estimates of diotic listening conditions from monaural WAV files. It was clearly demonstrated using a validation jury test that the revised time-varying loudness model was a significant improvement over the previously standardized approach.

  18. Respiration signals from photoplethysmography.

    Science.gov (United States)

    Nilsson, Lena M

    2013-10-01

    Pulse oximetry is based on the technique of photoplethysmography (PPG) wherein light transmitted through tissues is modulated by the pulse. In addition to variations in light modulation by the cardiac cycle, the PPG signal contains a respiratory modulation and variations associated with changing tissue blood volume of other origins. Cardiovascular, respiratory, and neural fluctuations in the PPG signal are of different frequencies and can all be characterized according to their sinusoidal components. PPG was described in 1937 to measure blood volume changes. The technique is today increasingly used, in part because of developments in semiconductor technology during recent decades that have resulted in considerable advances in PPG probe design. Artificial neural networks help to detect complex nonlinear relationships and are extensively used in electronic signal analysis, including PPG. Patient and/or probe-tissue movement artifacts are sources of signal interference. Physiologic variations such as vasoconstriction, a deep gasp, or yawn also affect the signal. Monitoring respiratory rates from PPG are often based on respiratory-induced intensity variations (RIIVs) contained in the baseline of the PPG signal. Qualitative RIIV signals may be used for monitoring purposes regardless of age, gender, anesthesia, and mode of ventilation. Detection of breaths in adult volunteers had a maximal error of 8%, and in infants the rates of overdetected and missed breaths using PPG were 1.5% and 2.7%, respectively. During central apnea, the rhythmic RIIV signals caused by variations in intrathoracic pressure disappear. PPG has been evaluated for detecting airway obstruction with a sensitivity of 75% and a specificity of 85%. The RIIV and the pulse synchronous PPG waveform are sensitive for detecting hypovolemia. The respiratory synchronous variation of the PPG pulse amplitude is an accurate predictor of fluid responsiveness. Pleth variability index is a continuous measure of the

  19. VLSI signal processing technology

    CERN Document Server

    Swartzlander, Earl

    1994-01-01

    This book is the first in a set of forthcoming books focussed on state-of-the-art development in the VLSI Signal Processing area. It is a response to the tremendous research activities taking place in that field. These activities have been driven by two factors: the dramatic increase in demand for high speed signal processing, especially in consumer elec­ tronics, and the evolving microelectronic technologies. The available technology has always been one of the main factors in determining al­ gorithms, architectures, and design strategies to be followed. With every new technology, signal processing systems go through many changes in concepts, design methods, and implementation. The goal of this book is to introduce the reader to the main features of VLSI Signal Processing and the ongoing developments in this area. The focus of this book is on: • Current developments in Digital Signal Processing (DSP) pro­ cessors and architectures - several examples and case studies of existing DSP chips are discussed in...

  20. Reduced dielectric response in spatially varying electric fields

    DEFF Research Database (Denmark)

    Hansen, Jesper Schmidt

    2015-01-01

    In this paper, the dynamical equation for polarization is derived. From this the dielectric response to a spatially varying electric field is analyzed showing a reduced response due to flux of polarization in the material. This flux is modeled as a diffusive process through linear constitutive...... relations between the flux and the gradient of the polarization. Comparison between the theory and molecular dynamics simulations confirms this effect. The effect is significant for small length scale electric field variations and the inclusion of the flux is thus important in nanoscale modeling...